Bio

Academic Appointments


Administrative Appointments


  • Sapp Family Provostial Professorship, Stanford University, Inaugural Chair Holder (2010 - Present)
  • David Starr Jordan Director, Stanford, Bio-X (2013 - Present)
  • Director, Bio-X (2007 - Present)

Honors & Awards


  • Pasarow Foundation Award in Neuropsychiatry Research, Pasarow Foundation (2013)
  • Sackler Prize for Distinguished Achievement in Developmental Psychobiology, Columbia University and Weil Cornell Medical School (2013)
  • Ralph Gerard Prize in Neuroscience, Society for Neuroscience (2011)
  • Elected Foreign Member, Royal Society, London, England (2011)
  • Physiological Society Prize Lecture, Physiological Society Prize Lecture Oxford England (2011)
  • Sapp Family Provostial Professorship, Stanford University Inaugural Chair Holder (2010)
  • Honorary Degree, James Watson School of Biological Sciences, Cold Spring Harbor Laboratory (2010)
  • Salpeter Lifetime Achievement Award, Society for Neuroscience (2009)
  • Gill Prize in Neuroscience, Indiana University (2006)
  • Honorary Degree, Federal Institute of Technology, Lausanne, Switzerland (2002)
  • 2000 Weizmann Women and Science Award, Weizmann Institute (2000)
  • Elected Member, Institute of Medicine, National Academy of Sciences (1999)
  • Elected Member, American Philosophical Society (1997)
  • Alcon Award for Outstanding Contributions to Vision Research, Alcon Research Institutre (1997)
  • Elected Fellow, American Academy of Arts and Sciences (1992)
  • Charles A. Dana Award for Pioneering Achievement in Health and Education, Charles A. Dana Foundation (1995)
  • Elected Member, National Academy of Sciences (1995)
  • President, Society for Neuroscience (1994)
  • Elected Member, European Academy of Sciences and Arts (1992)

Professional Education


  • Postdoctoral, Harvard Medical School, Neurobiology (1978)
  • Ph.D., Harvard University, Neurobiology (1976)
  • M.Phil, University College London, Physiology (1971)
  • B.A., Radcliffe College, Cambridge, MA, Chemistry (1969)

Research & Scholarship

Current Research and Scholarly Interests


By studying the visual system of mammals, the Shatz Lab discovered that adult wiring emerges from dynamic interactions between neurons involving neural function and synaptic plasticity. Even before birth and long before vision, the eye spontaneously generates and sends coordinated patterns of neural activity to the brain. Blocking this activity in utero, or preventing vision after birth, disrupts normal tuning up of circuits and brain wiring. In turn, neural activity regulates the expression of genes involved in the process of circuit tuning. To discover cell and molecular underpinnings of circuit tuning, her lab has conducted functional screens for genes regulated by neural activity. Among these genes is the MHC (major histocompatibility) Class I family. This finding was very surprising because these genes- HLA genes in humans- are involved in cellular immunity and were previously not thought to be expressed by neurons at all! The Shatz Lab showed that other components of a signaling system for Class I MHC are also present in neurons, including a novel receptor, PirB. By studying and/or generating knockout mice, the lab is exploring a role for these molecules in synaptic plasticity, learning, memory and neurological disorders. The lab employs a variety of approaches in these studies, ranging from molecular biology to slice electrophysiology to in vivo imaging to behavior. Research has relevance not only for understanding brain wiring and developmental disorders such as Autism and Schizphrenia, but also for understanding how the nervous and immune systems interact.

Teaching

2013-14 Courses


Postdoctoral Advisees


Graduate and Fellowship Programs


Publications

Journal Articles


  • PirB regulates a structural substrate for cortical plasticity PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Djurisic, M., Vidal, G. S., Mann, M., Aharon, A., Kim, T., Santos, A. F., Zuo, Y., Huebener, M., Shatz, C. J. 2013; 110 (51): 20771-20776

    Abstract

    Experience-driven circuit changes underlie learning and memory. Monocular deprivation (MD) engages synaptic mechanisms of ocular dominance (OD) plasticity and generates robust increases in dendritic spine density on L5 pyramidal neurons. Here we show that the paired immunoglobulin-like receptor B (PirB) negatively regulates spine density, as well as the threshold for adult OD plasticity. In PirB(-/-) mice, spine density and stability are significantly greater than WT, associated with higher-frequency miniature synaptic currents, larger long-term potentiation, and deficient long-term depression. Although MD generates the expected increase in spine density in WT, in PirB(-/-) this increase is occluded. In adult PirB(-/-), OD plasticity is larger and more rapid than in WT, consistent with the maintenance of elevated spine density. Thus, PirB normally regulates spine and excitatory synapse density and consequently the threshold for new learning throughout life.

    View details for DOI 10.1073/pnas.1321092110

    View details for Web of Science ID 000328548600089

    View details for PubMedID 24302763

  • Human LilrB2 is an amyloid-beta receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer’s model SCIENCE Kim, T., Vidal, G., Djurisic, M., William, C., Birnbaum, M., et al 2013; 341: 1399-1404
  • Synaptic Plasticity Defect Following Visual Deprivation in Alzheimer's Disease Model Transgenic Mice JOURNAL OF NEUROSCIENCE William, C. M., Andermann, M. L., Goldey, G. J., Roumis, D. K., Reid, R. C., Shatz, C. J., Albers, M. W., Frosch, M. P., Hyman, B. T. 2012; 32 (23): 8004-8011

    Abstract

    Amyloid-? (A?)-induced changes in synaptic function in experimental models of Alzheimer's disease (AD) suggest that A? generation and accumulation may affect fundamental mechanisms of synaptic plasticity. To test this hypothesis, we examined the effect of APP overexpression on a well characterized, in vivo, developmental model of systems-level plasticity, ocular dominance plasticity. Following monocular visual deprivation during the critical period, mice that express mutant alleles of amyloid precursor protein (APPswe) and Presenilin1 (PS1dE9), as well as mice that express APPswe alone, lack ocular dominance plasticity in visual cortex. Defects in the spatial extent and magnitude of the plastic response are evident using two complementary approaches, Arc induction and optical imaging of intrinsic signals in awake mice. This defect in a classic paradigm of systems level synaptic plasticity shows that A? overexpression, even early in postnatal life, can perturb plasticity in cerebral cortex, and supports the idea that decreased synaptic plasticity due to elevated A? exposure contributes to cognitive impairment in AD.

    View details for DOI 10.1523/JNEUROSCI.5369-11.2012

    View details for Web of Science ID 000305091800024

    View details for PubMedID 22674275

  • Neuroprotection from Stroke in the Absence of MHCI or PirB NEURON Adelson, J. D., Barreto, G. E., Xu, L., Kim, T., Brott, B. K., Ouyang, Y., Naserke, T., Djurisic, M., Xiong, X., Shatz, C. J., Giffard, R. G. 2012; 73 (6): 1100-1107

    Abstract

    Recovery from stroke engages mechanisms of neural plasticity. Here we examine a role for MHC class I (MHCI) H2-Kb and H2-Db, as well as PirB receptor. These molecules restrict synaptic plasticity and motor learning in the healthy brain. Stroke elevates neuronal expression not only of H2-Kb and H2-Db, but also of PirB and downstream signaling. KbDb knockout (KO) or PirB KO mice have smaller infarcts and enhanced motor recovery. KO hippocampal organotypic slices, which lack an intact peripheral immune response, have less cell death after in vitro ischemia. In PirB KO mice, corticospinal projections from the motor cortex are enhanced, and the reactive astrocytic response is dampened after MCAO. Thus, molecules that function in the immune system act not only to limit synaptic plasticity in healthy neurons, but also to exacerbate brain injury after ischemia. These results suggest therapies for stroke by targeting MHCI and PirB.

    View details for DOI 10.1016/j.neuron.2012.01.020

    View details for Web of Science ID 000301998700008

    View details for PubMedID 22445338

  • Classical MHCI Molecules Regulate Retinogeniculate Refinement and Limit Ocular Dominance Plasticity NEURON Datwani, A., McConnell, M. J., Kanold, P. O., Micheva, K. D., Busse, B., Shamloo, M., Smith, S. J., Shatz, C. J. 2009; 64 (4): 463-470

    Abstract

    Major histocompatibility complex class I (MHCI) genes were discovered unexpectedly in healthy CNS neurons in a screen for genes regulated by neural activity. In mice lacking just 2 of the 50+ MHCI genes H2-K(b) and H2-D(b), ocular dominance (OD) plasticity is enhanced. Mice lacking PirB, an MHCI receptor, have a similar phenotype. H2-K(b) and H2-D(b) are expressed not only in visual cortex, but also in lateral geniculate nucleus (LGN), where protein localization correlates strongly with synaptic markers and complement protein C1q. In K(b)D(b-/-) mice, developmental refinement of retinogeniculate projections is impaired, similar to C1q(-/-) mice. These phenotypes in K(b)D(b-/-) mice are strikingly similar to those in beta2 m(-/-)TAP1(-/-) mice, which lack cell surface expression of all MHCIs, implying that H2-K(b) and H2-D(b) can account for observed changes in synapse plasticity. H2-K(b) and H2-D(b) ligands, signaling via neuronal MHCI receptors, may enable activity-dependent remodeling of brain circuits during developmental critical periods.

    View details for DOI 10.1016/j.neuron.2009.10.015

    View details for Web of Science ID 000272378900005

    View details for PubMedID 19945389

  • MHC Class I: An Unexpected Role in Neuronal Plasticity NEURON Shatz, C. J. 2009; 64 (1): 40-45

    Abstract

    For the nervous system to translate experience into memory and behavior, lasting structural change at synapses must occur. This requirement is clearly evident during critical periods of activity-dependent neural development, and accumulating evidence has established a surprising role for the major histocompatibility complex class I (MHCI) proteins in this process.

    View details for DOI 10.1016/j.neuron.2009.09.044

    View details for Web of Science ID 000271454400009

    View details for PubMedID 19840547

  • Synaptogenesis in Purified Cortical Subplate Neurons CEREBRAL CORTEX McKellar, C. E., Shatz, C. J. 2009; 19 (8): 1723-1737

    Abstract

    An ideal preparation for investigating events during synaptogenesis would be one in which synapses are sparse, but can be induced at will using a rapid, exogenous trigger. We describe a culture system of immunopurified subplate neurons in which synaptogenesis can be triggered, providing the first homogeneous culture of neocortical neurons for the investigation of synapse development. Synapses in immunopurified rat subplate neurons are sparse, and can be induced by a 48-h exposure to feeder layers of neurons and glia, an induction more rapid than any previously reported. Induced synapses are electrophysiologically functional and ultrastructurally normal. Microarray and real-time PCR experiments reveal a new program of gene expression accompanying synaptogenesis. Surprisingly few known synaptic genes are upregulated during the first 24 h of synaptogenesis; Gene Ontology annotation reveals a preferential upregulation of synaptic genes only at a later time. In situ hybridization confirms that some of the genes regulated in cultures are also expressed in the developing cortex. This culture system provides both a means of studying synapse formation in a homogeneous population of cortical neurons, and better synchronization of synaptogenesis, permitting the investigation of neuron-wide events following the triggering of synapse formation.

    View details for DOI 10.1093/cercor/bhn194

    View details for Web of Science ID 000267888000003

    View details for PubMedID 19029062

  • Co-regulation of ocular dominance plasticity and NMDA receptor subunit expression in glutamic acid decarboxylase-65 knock-out mice JOURNAL OF PHYSIOLOGY-LONDON Kanold, P. O., Kim, Y. A., GrandPre, T., Shatz, C. J. 2009; 587 (12): 2857-2867

    Abstract

    Experience can shape cortical circuits, especially during critical periods for plasticity. In visual cortex, imbalance of activity from the two eyes during the critical period shifts ocular dominance (OD) towards the more active eye. Inhibitory circuits are crucial in this process: OD plasticity is absent in GAD65KO mice that show diminished inhibition. This defect can be rescued by application of benzodiazepines, which increase GABAergic signalling. However, it is unknown how such changes in inhibition might disrupt and then restore OD plasticity. Since NMDA dependent synaptic plasticity mechanisms are also known to contribute to OD plasticity, we investigated whether NMDA receptor levels and function are also altered in GAD65KO. There are reduced NR2A levels and slower NMDA currents in visual cortex of GAD65KO mice. Application of benzodiazepines, which rescues OD plasticity, also increases NR2A levels. Thus it appears as if OD plasticity can be restored by adding a critical amount of excitatory transmission through NR2A-containing NMDA receptors. Together, these observations can unify competing ideas of how OD plasticity is regulated: changes in either inhibition or excitation would engage homeostatic mechanisms that converge to regulate NMDA receptors, thereby enabling plasticity mechanisms and also ensuring circuit stability.

    View details for DOI 10.1113/jphysiol.2009.171215

    View details for Web of Science ID 000266981400020

    View details for PubMedID 19406876

  • H2-K-b and H2-D-b regulate cerebellar long-term depression and limit motor learning PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA McConnell, M. J., Huang, Y. H., Datwani, A., Shatz, C. J. 2009; 106 (16): 6784-6789

    Abstract

    There are more than 50 class I MHC (MHCI) molecules in the mouse genome, some of which are now known to be expressed in neurons; however, the role of classical MHCI molecules in synaptic plasticity is unknown. We report that the classical MHCI molecules, H2-K(b) and H2-D(b), are co-expressed by Purkinje cells (PCs). In the cerebellum of mice deficient for both H2-K(b) and H2-D(b) (K(b)D(b-/-)), there is a lower threshold for induction of long-term depression (LTD) at parallel fiber to PC synapses. This change may be a result of additional glutamate release observed at K(b)D(b-/-) CF to PC synapses, which are thought to "train" the cerebellar circuit. A behavioral correlate of cerebellar LTD is motor learning; acquisition and retention of a Rotarod behavioral task is significantly better in K(b)D(b-/-) mice than in WT cohorts. These physiological and behavioral phenotypes in K(b)D(b-/-) mice reveal a surprising role for classical MHCI molecules in synaptic plasticity and motor learning.

    View details for DOI 10.1073/pnas.0902018106

    View details for Web of Science ID 000265506800065

    View details for PubMedID 19346486

  • PirB is a Functional Receptor for Myelin Inhibitors of Axonal Regeneration SCIENCE Atwal, J. K., Pinkston-Gosse, J., Syken, J., Stawicki, S., Wu, Y., Shatz, C., Tessier-Lavigne, M. 2008; 322 (5903): 967-970

    Abstract

    A major barrier to regenerating axons after injury in the mammalian central nervous system is an unfavorable milieu. Three proteins found in myelin--Nogo, MAG, and OMgp--inhibit axon regeneration in vitro and bind to the glycosylphosphatidylinositol-anchored Nogo receptor (NgR). However, genetic deletion of NgR has only a modest disinhibitory effect, suggesting that other binding receptors for these molecules probably exist. With the use of expression cloning, we have found that paired immunoglobulin-like receptor B (PirB), which has been implicated in nervous system plasticity, is a high-affinity receptor for Nogo, MAG, and OMgp. Interfering with PirB activity, either with antibodies or genetically, partially rescues neurite inhibition by Nogo66, MAG, OMgp, and myelin in cultured neurons. Blocking both PirB and NgR activities leads to near-complete release from myelin inhibition. Our results implicate PirB in mediating regeneration block, identify PirB as a potential target for axon regeneration therapies, and provide an explanation for the similar enhancements of visual system plasticity in PirB and NgR knockout mice.

    View details for DOI 10.1126/science.1161151

    View details for Web of Science ID 000260674100054

    View details for PubMedID 18988857

  • Regulation of CNS synapses by neuronal MHC class I PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Goddard, C. A., Butts, D. A., Shatz, C. J. 2007; 104 (16): 6828-6833

    Abstract

    Until recently, neurons in the healthy brain were considered immune-privileged because they did not appear to express MHC class I (MHCI). However, MHCI mRNA was found to be regulated by neural activity in the developing visual system and has been detected in other regions of the uninjured brain. Here we show that MHCI regulates aspects of synaptic function in response to activity. MHCI protein is colocalized postsynaptically with PSD-95 in dendrites of hippocampal neurons. In vitro, whole-cell recordings of hippocampal neurons from beta2m/TAP1 knockout (KO) mice, which have reduced MHCI surface levels, indicate a 40% increase in mini-EPSC (mEPSC) frequency. mEPSC frequency is also increased 100% in layer 4 cortical neurons. Similarly, in KO hippocampal cultures, there is a modest increase in the size of presynaptic boutons relative to WT, whereas postsynaptic parameters (PSD-95 puncta size and mEPSC amplitude) are normal. In EM of intact hippocampus, KO synapses show a corresponding increase in vesicles number. Finally, KO neurons in vitro fail to respond normally to TTX treatment by scaling up synaptic parameters. Together, these results suggest that postsynaptically localized MHCl acts in homeostatic regulation of synaptic function and morphology during development and in response to activity blockade. The results also imply that MHCI acts retrogradely across the synapse to translate activity into lasting change in structure.

    View details for DOI 10.1073/pnas.0702023104

    View details for Web of Science ID 000245869200061

    View details for PubMedID 17420446

  • A burst-based "Hebbian" learning rule at retinogenicu late synapses links retinal waves to activity-dependent refinement PLOS BIOLOGY Butts, D. A., Kanold, P. O., Shatz, C. J. 2007; 5 (3): 651-661

    Abstract

    Patterned spontaneous activity in the developing retina is necessary to drive synaptic refinement in the lateral geniculate nucleus (LGN). Using perforated patch recordings from neurons in LGN slices during the period of eye segregation, we examine how such burst-based activity can instruct this refinement. Retinogeniculate synapses have a novel learning rule that depends on the latencies between pre- and postsynaptic bursts on the order of one second: coincident bursts produce long-lasting synaptic enhancement, whereas non-overlapping bursts produce mild synaptic weakening. It is consistent with "Hebbian" development thought to exist at this synapse, and we demonstrate computationally that such a rule can robustly use retinal waves to drive eye segregation and retinotopic refinement. Thus, by measuring plasticity induced by natural activity patterns, synaptic learning rules can be linked directly to their larger role in instructing the patterning of neural connectivity.

    View details for DOI 10.1371/journal.pbio.0050061

    View details for Web of Science ID 000245243500022

    View details for PubMedID 17341130

  • PirB restricts ocular-dominance plasticity in visual cortex SCIENCE Syken, J., GrandPre, T., Kanold, P. O., Shatz, C. J. 2006; 313 (5794): 1795-1800

    Abstract

    Experience can alter synaptic connectivity throughout life, but the degree of plasticity present at each age is regulated by mechanisms that remain largely unknown. Here, we demonstrate that Paired-immunoglobulin-like receptor B (PirB), a major histocompatibility complex class I (MHCI) receptor, is expressed in subsets of neurons throughout the brain. Neuronal PirB protein is associated with synapses and forms complexes with the phosphatases Shp-1 and Shp-2. Soluble PirB fusion protein binds to cortical neurons in an MHCI-dependent manner. In mutant mice lacking functional PirB, cortical ocular-dominance plasticity is more robust at all ages. Thus, an MHCI receptor is expressed in central nervous system neurons and functions to limit the extent of experience-dependent plasticity in the visual cortex throughout life. PirB is also expressed in many other regions of the central nervous system, suggesting that it may function broadly to stabilize neural circuits.

    View details for DOI 10.1126/science.1128232

    View details for Web of Science ID 000240655700051

    View details for PubMedID 16917027

  • Subplate neurons regulate maturation of cortical inhibition and outcome of ocular dominance plasticity NEURON Kanold, P. O., Shatz, C. J. 2006; 51 (5): 627-638

    Abstract

    Synaptic plasticity during critical periods of development requires intact inhibitory circuitry. We report that subplate neurons are needed both for maturation of inhibition and for the proper sign of ocular dominance (OD) plasticity. Removal of subplate neurons prevents the developmental upregulation of genes involved in mature, fast GABAergic transmission in cortical layer 4, including GABA receptor subunits and KCC2, and thus prevents the switch to a hyperpolarizing effect of GABA. To understand the implications of these changes, a realistic circuit model was formulated. Simulations predicted that without subplate neurons, monocular deprivation (MD) paradoxically favors LGN axons representing the deprived (less active) eye, exactly what was then observed experimentally. Simulations also account for published results showing that OD plasticity requires mature inhibition. Thus, subplate neurons regulate molecular machinery required to establish an adult balance of excitation and inhibition in layer 4, and thereby influence the outcome of OD plasticity.

    View details for DOI 10.1016/j.neuron.2006.07.008

    View details for Web of Science ID 000240623400011

    View details for PubMedID 16950160

  • Effects of visual experience on activity-dependent gene regulation in cortex NATURE NEUROSCIENCE Majdan, M., Shatz, C. J. 2006; 9 (5): 650-659

    Abstract

    There are critical periods in development when sensory experience directs the maturation of synapses and circuits within neocortex. We report that the critical period in mouse visual cortex has a specific molecular logic of gene regulation. Four days of visual deprivation regulated one set of genes during the critical period, and different sets before or after. Dark rearing perturbed the regulation of these age-specific gene sets. In addition, a 'common gene set', comprised of target genes belonging to a mitogen-activated protein (MAP) kinase signaling pathway, was regulated by vision at all ages but was impervious to prior history of sensory experience. Together, our results demonstrate that vision has dual effects on gene regulation in visual cortex and that sensory experience is needed for the sequential acquisition of age-specific, but not common, gene sets. Thus, a dynamic interplay between experience and gene expression drives activity-dependent circuit maturation.

    View details for DOI 10.1038/nn1674

    View details for Web of Science ID 000237417200016

    View details for PubMedID 16582906

  • Lawrence C. Katz (1956-2005) - Obituary NATURE Shatz, C. J. 2006; 439 (7073): 152-152

    View details for DOI 10.1038/439152a

    View details for Web of Science ID 000234538400028

    View details for PubMedID 16407942

  • Multiple periods of functional ocular dominance plasticity in mouse visual cortex NATURE NEUROSCIENCE Tagawa, Y., Kanold, P. O., Majdan, M., Shatz, C. J. 2005; 8 (3): 380-388

    Abstract

    The precise period when experience shapes neural circuits in the mouse visual system is unknown. We used Arc induction to monitor the functional pattern of ipsilateral eye representation in cortex during normal development and after visual deprivation. After monocular deprivation during the critical period, Arc induction reflects ocular dominance (OD) shifts within the binocular zone. Arc induction also reports faithfully expected OD shifts in cat. Shifts towards the open eye and weakening of the deprived eye were seen in layer 4 after the critical period ends and also before it begins. These shifts include an unexpected spatial expansion of Arc induction into the monocular zone. However, this plasticity is not present in adult layer 6. Thus, functionally assessed OD can be altered in cortex by ocular imbalances substantially earlier and far later than expected.

    View details for DOI 10.1038/nn1410

    View details for Web of Science ID 000227354600024

    View details for PubMedID 15723060

  • Changing scientific publishing SCIENCE RAFF, M. C., Stevens, C. F., Roberts, K., Shatz, C. J., Newsome, W. T. 2004; 305 (5686): 945-946

    View details for Web of Science ID 000223250700017

    View details for PubMedID 15310878

  • Immune signalling in neural development, synaptic plasticity and disease NATURE REVIEWS NEUROSCIENCE Boulanger, L. M., Shatz, C. J. 2004; 5 (7): 521-531

    View details for DOI 10.1038/nrn1428

    View details for Web of Science ID 000222435000011

    View details for PubMedID 15208694

  • Expression of T cell receptor beta locus in central nervous system neurons PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Syken, J., Shatz, C. J. 2003; 100 (22): 13048-13053

    Abstract

    MHC class I proteins are cell-surface ligands that bind to T cell receptors and other immunoreceptors and act to regulate the activation state of immune cells. Recent work has shown that MHC class I genes and CD3zeta, an obligate component of T cell receptors, are expressed in neurons, are regulated by neuronal activity, and function in neuronal development and plasticity. A search for additional neuronally expressed T cell receptor components has revealed that the T cell antigen receptor beta (TCRbeta) locus is expressed in neurons of the murine central nervous system and that this expression is dynamically regulated over development. In neonates, expression is most abundant in various thalamic nuclei. At later ages and in adults, thalamic expression fades and cortical expression is robust, particularly in layer 6. In T cells, protein-encoding transcripts are produced only after recombination of the TCRbeta genomic locus, which joins variable, diversity, and joining regions, a process that creates much of the diversity of the immune system. We detect no genomic recombination in neurons. Rather, transcripts begin in regions upstream of several joining regions, and are spliced to constant region segments. One of the transcripts encodes a hypothetical 207-aa, 23-kDa protein, which includes the TCRbeta J2.7 region, and the entire C region. These observations suggest that TCRbeta may function in neurons.

    View details for DOI 10.1073/pnas.1735415100

    View details for Web of Science ID 000186301100097

    View details for PubMedID 14569018

  • Role of subplate neurons in functional maturation of visual cortical columns SCIENCE Kanold, P. O., Kara, P., Reid, R. C., Shatz, C. J. 2003; 301 (5632): 521-525

    Abstract

    The subplate forms a transient circuit required for development of connections between the thalamus and the cerebral cortex. When subplate neurons are ablated, ocular dominance columns do not form in the visual cortex despite the robust presence of thalamic axons in layer 4. We show that subplate ablation also prevents formation of orientation columns. Visual responses are weak and poorly tuned to orientation. Furthermore, thalamocortical synaptic transmission fails to strengthen, whereas intracortical synapses are unaffected. Thus, subplate circuits are essential not only for the anatomical segregation of thalamic inputs but also for key steps in synaptic remodeling and maturation needed to establish the functional architecture of visual cortex.

    View details for Web of Science ID 000184340500044

    View details for PubMedID 12881571

  • Selective vulnerability of subplate neurons after early neonatal hypoxia-ischemia JOURNAL OF NEUROSCIENCE McQuillen, P. S., Sheldon, R. A., Shatz, C. J., Ferriero, D. M. 2003; 23 (8): 3308-3315

    Abstract

    Neonatal hypoxia-ischemia in the preterm human leads to selective injury to the subcortical developing white matter, which results in periventricular leukomalacia (PVL), a condition associated with abnormal neurodevelopment. Maturation-dependent vulnerability of late oligodendrocyte progenitors is thought to account for the cellular basis of this condition. A high frequency of cognitive and sensory deficits with decreasing gestational age suggests pervasive abnormalities of cortical development. In a neonatal rat model of hypoxic-ischemic injury that produces the characteristic pattern of subcortical injury associated with human PVL, selective subplate neuron death is seen. The premature subplate neuron death occurs after thalamic axons have reached their targets in cortex. Thus, as expected, thalamocortical connections form normally, including patterned connections to somatosensory cortex. However, deficits in motor function still occur, as in babies with PVL. Subplate neuron cell death in PVL provides another mechanism for abnormal neurodevelopment after neonatal hypoxia-ischemia.

    View details for Web of Science ID 000182475200025

    View details for PubMedID 12716938

  • A novel role for p75NTR in subplate growth cone complexity and visual thalamocortical innervation JOURNAL OF NEUROSCIENCE McQuillen, P. S., DeFreitas, M. F., Zada, G., Shatz, C. J. 2002; 22 (9): 3580-3593

    Abstract

    In cortical development, subplate axons pioneer the pathway from neocortex to the internal capsule, leading to the proposal that they are required for subsequent area-specific innervation of cortex by thalamic axons. A role for p75 neutrophin receptor (NTR) in area-specific thalamic innervation of cortex is suggested by the observation that p75NTR expression is restricted to subplate neurons in a low-rostral to high-caudal gradient throughout the period of thalamocortical innervation. In vitro, neurotrophin 3 binding to p75NTR increases neurite length and filopodial formation of immunopurified subplate neurons, suggesting a role for p75NTR in subplate growth cone morphology and function in vivo. Consistent with this idea, subplate growth cones have markedly fewer filopodia in mice lacking p75NTR than in wild type mice. Despite this gross morphologic defect, many subplate axons in knock-out mice pioneer the projection to the internal capsule as they do in wild-type mice. However a few subplate axons in the knock-out mice make ectopic projections rostral in the intermediate zone and frontal cortex. Concomitant with the altered morphology of subplate growth cones, mice lacking p75NTR have diminished innervation of visual cortex from the lateral geniculate nucleus, with markedly reduced or absent connections in 48% of knock-out mice. Thalamic projections to auditory and somatosensory cortex are normal, consistent with the gradient of p75NTR expression. Our present results are unusual in that they argue that p75NTR functions in a novel way in subplate neurons, that is, in growth cone morphology and function rather than in axon extension or neuronal survival.

    View details for Web of Science ID 000175296200035

    View details for PubMedID 11978834

  • An instructive role for retinal waves in the development of retinogeniculate connectivity NEURON Stellwagen, D., Shatz, C. J. 2002; 33 (3): 357-367

    Abstract

    A central hypothesis of neural development is that patterned activity drives the refinement of initially imprecise connections. We have examined this hypothesis directly by altering the frequency of spontaneous waves of activity that sweep across the mammalian retina prior to vision. Activity levels were increased in vivo using agents that elevate cAMP. When one eye is made more active, its layer within the LGN is larger despite the other eye having normal levels of activity. Remarkably, when the frequency of retinal waves is increased in both eyes, normally sized layers form. Because relative, rather than absolute, levels of activity between the eyes regulate the amount of LGN territory devoted to each eye, we conclude that activity acts instructively to guide binocular segregation during development.

    View details for Web of Science ID 000173643200007

    View details for PubMedID 11832224

  • Neuronal plasticity and cellular immunity: shared molecular mechanisms CURRENT OPINION IN NEUROBIOLOGY Boulanger, L. M., Huh, G. S., Shatz, C. J. 2001; 11 (5): 568-578

    Abstract

    It is becoming evident that neurons express an unusual number of molecules that were originally thought to be specific to immune functions. One such molecule, class I major histocompatibility complex, is required in the activity-dependent refinement and plasticity of connections in the developing and adult central nervous system, demonstrating that molecules can perform critical roles in both systems. Recent studies reveal striking parallels between cellular signaling mechanisms in the immune and nervous systems that may provide unexpected insights into the development, function, and diseases of both systems.

    View details for Web of Science ID 000171712000007

    View details for PubMedID 11595490

  • A novel p75NTR signaling pathway promotes survival, not death, of immunopurified neocortical subplate neurons JOURNAL OF NEUROSCIENCE DeFreitas, M. F., McQuillen, P. S., Shatz, C. J. 2001; 21 (14): 5121-5129

    Abstract

    Subplate neurons of mammalian neocortex undergo pronounced cell death postnatally, long after they have matured and become incorporated into functional cortical circuits. They express the p75 neurotrophin receptor (p75NTR), which is known to signal cell death in some types of neurons via the activation of sphingomyelinase and the concomitant increase in the sphingolipid ceramide. To evaluate the role of p75NTR in subplate neurons, they were immunopurified and cultured in vitro. Contrary to its known function as a death receptor, ligand binding to p75NTR promotes subplate neuron survival. Moreover, p75NTR-dependent survival is blocked by inhibition of ceramide synthesis and rescued by addition of its precursor sphingomyelin. Inhibition of Trk signaling does not block survival, nor is Trk signaling alone sufficient to promote survival. Thus, ligand-dependent p75NTR regulation of the ceramide pathway mediates survival in certain neurons and may represent an important target for neuroprotective drugs in degenerative diseases involving p75NTR-expressing neurons, such as Alzheimer's disease.

    View details for Web of Science ID 000169692800021

    View details for PubMedID 11438587

  • Functional requirement for class I MHC in CNS development and plasticity SCIENCE Huh, G. S., Boulanger, L. M., Du, H. P., Riquelme, P. A., Brotz, T. M., Shatz, C. J. 2000; 290 (5499): 2155-2159

    Abstract

    Class I major histocompatibility complex (class I MHC) molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, long-term structural and synaptic modifications. Here, we show that in mice genetically deficient for cell surface class I MHC or for a class I MHC receptor component, CD3zeta, refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) is enhanced, and long-term depression (LTD) is absent. Specific class I MHC messenger RNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrate an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system (CNS).

    View details for Web of Science ID 000165870600059

    View details for PubMedID 11118151

  • Netrin-1 promotes thalamic axon growth and is required for proper development of the thalamocortical projection JOURNAL OF NEUROSCIENCE Braisted, J. E., Catalano, S. M., Stimac, R., Kennedy, T. E., Tessier-Lavigne, M., Shatz, C. J., O'Leary, D. D. 2000; 20 (15): 5792-5801

    Abstract

    The thalamocortical axon (TCA) projection originates in dorsal thalamus, conveys sensory input to the neocortex, and has a critical role in cortical development. We show that the secreted axon guidance molecule netrin-1 acts in vitro as an attractant and growth promoter for dorsal thalamic axons and is required for the proper development of the TCA projection in vivo. As TCAs approach the hypothalamus, they turn laterally into the ventral telencephalon and extend toward the cortex through a population of netrin-1-expressing cells. DCC and neogenin, receptors implicated in mediating the attractant effects of netrin-1, are expressed in dorsal thalamus, whereas unc5h2 and unc5h3, netrin-1 receptors implicated in repulsion, are not. In vitro, dorsal thalamic axons show biased growth toward a source of netrin-1, which can be abolished by netrin-1-blocking antibodies. Netrin-1 also enhances overall axon outgrowth from explants of dorsal thalamus. The biased growth of dorsal thalamic axons toward the internal capsule zone of ventral telencephalic explants is attenuated, but not significantly, by netrin-1-blocking antibodies, suggesting that it releases another attractant activity for TCAs in addition to netrin-1. Analyses of netrin-1 -/- mice reveal that the TCA projection through the ventral telencephalon is disorganized, their pathway is abnormally restricted, and fewer dorsal thalamic axons reach cortex. These findings demonstrate that netrin-1 promotes the growth of TCAs through the ventral telencephalon and cooperates with other guidance cues to control their pathfinding from dorsal thalamus to cortex.

    View details for Web of Science ID 000088354000032

    View details for PubMedID 10908620

  • Dynamic regulation of BDNF and NT-3 expression during visual system development JOURNAL OF COMPARATIVE NEUROLOGY Lein, E. S., Hohn, A., Shatz, C. J. 2000; 420 (1): 1-18

    Abstract

    Recent studies have proposed roles for neurotrophins in the formation and plasticity of ocular dominance columns as well as in the regulation of dendritic arborization in visual cortex of higher mammals. To assess potential roles for neurotrophins in these processes, we have examined the developmental expression of BDNF and NT-3 mRNA in the cat's visual system using in situ hybridization. BDNF and NT-3 mRNAs are dynamically regulated in many CNS structures during embryonic and postnatal development, and both mRNAs undergo striking developmental changes in laminar specificity and levels of expression within primary visual cortex during the critical period for ocular dominance column formation. Within visual cortex, BDNF mRNA is found in neurons in deep cortical layers (5 and 6) prior to eye opening, and in both deep and superficial layers (2 and 3) shortly afterwards. Within layer 4, the target of thalamocortical axons, BDNF mRNA is low initially and rises to high levels by the end of the critical period for ocular dominance column formation. NT-3 mRNA is first detectable in small stellate neurons at the base of layer 4 (4c) after eye opening, and levels decrease near the end of the critical period. BDNF and NT-3 mRNAs can be detected in the lateral geniculate nucleus at birth, and levels peak during the critical period. In both structures, BDNF mRNA expression is maintained into adulthood, while NT-3 is undetectable in the adult. The presence and dynamic regulation of these neurotrophins in visual structures is consistent with suggested roles for both of these neurotrophins in axonal and dendritic remodeling known to accompany the formation of ocular dominance columns.

    View details for Web of Science ID 000086207000001

    View details for PubMedID 10745216

  • Rapid regulation of brain-derived neurotrophic factor mRNA within eye-specific circuits during ocular dominance column formation JOURNAL OF NEUROSCIENCE Lein, E. S., Shatz, C. J. 2000; 20 (4): 1470-1483

    Abstract

    The neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a candidate retrograde signaling molecule for geniculocortical axons during the formation of ocular dominance columns. Here we examined whether neuronal activity can regulate BDNF mRNA in eye-specific circuits in the developing cat visual system. Dark-rearing throughout the critical period for ocular dominance column formation decreases levels of BDNF mRNA within primary visual cortex, whereas short-term (2 d) binocular blockade of retinal activity with tetrodotoxin (TTX) downregulates BDNF mRNA within the lateral geniculate nucleus (LGN) and visual cortical areas. Brief (6 hr to 2 d) monocular TTX blockade during the critical period and also in adulthood causes downregulation in appropriate eye-specific laminae in the LGN and ocular dominance columns within primary visual cortex. Monocular TTX blockade at postnatal day 23 also downregulates BDNF mRNA in a periodic fashion, consistent with recent observations that ocular dominance columns can be detected at these early ages by physiological methods. In contrast, 10 d monocular TTX during the critical period does not cause a lasting decrease in BDNF mRNA expression in columns pertaining to the treated eye, consistent with the nearly complete shift in physiological response properties of cortical neurons in favor of the unmanipulated eye known to result from long-term monocular deprivation. These observations demonstrate that BDNF mRNA levels can provide an accurate "molecular readout" of the activity levels of cortical neurons and are consistent with a highly local action of BDNF in strengthening and maintaining active synapses during ocular dominance column formation.

    View details for Web of Science ID 000085181200021

    View details for PubMedID 10662837

  • Subplate neuron ablation alters neurotrophin expression and ocular dominance column formation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lein, E. S., Finney, E. M., McQuillen, P. S., Shatz, C. J. 1999; 96 (23): 13491-13495

    Abstract

    Ocular dominance column formation in visual cortex depends on both the presence of subplate neurons and the endogenous expression of neurotrophins. Here we show that deletion of subplate neurons, which supply glutamatergic inputs to visual cortex, leads to a paradoxical increase in brain-derived neurotrophic factor mRNA in the same region of visual cortex in which ocular dominance columns are absent. Subplate neuron ablation also increases glutamic acid decarboxylase-67 levels, indicating an alteration in cortical inhibition. These observations imply a role for this special class of neurons in modulating activity-dependent competition by regulating levels of neurotrophins and excitability within a developing cortical circuit.

    View details for Web of Science ID 000083649400093

    View details for PubMedID 10557348

  • Dynamics of retinal waves are controlled by cyclic AMP NEURON Stellwagen, D., Shatz, C. J., Feller, M. B. 1999; 24 (3): 673-685

    Abstract

    Waves of spontaneous activity sweep across the developing mammalian retina and influence the pattern of central connections made by ganglion cell axons. These waves are driven by synaptic input from amacrine cells. We show that cholinergic synaptic transmission during waves is not blocked by TTX, indicating that release from starburst amacrine cells is independent of sodium action potentials. The spatiotemporal properties of the waves are regulated by endogenous release of adenosine, which sets intracellular cAMP levels through activation of A2 receptors present on developing amacrine and ganglion cells. Increasing cAMP levels increase the size, speed, and frequency of the waves. Conversely, inhibiting adenylate cyclase or PKA prevents wave activity. Together, these results imply a novel mechanism in which levels of cAMP within an immature retinal circuit regulate the precise spatial and temporal patterns of spontaneous neural activity.

    View details for Web of Science ID 000083913000022

    View details for PubMedID 10595518

  • Dynamic regulation of cpg15 during activity-dependent synaptic development in the mammalian visual system JOURNAL OF NEUROSCIENCE Corriveau, R. A., Shatz, C. J., Nedivi, E. 1999; 19 (18): 7999-8008

    Abstract

    During visual system development, neural activity regulates structural changes in connectivity including axonal branching and dendritic growth. Here we have examined a role for the candidate plasticity gene 15 (cpg15), which encodes an activity-regulated molecule that can promote dendritic growth, in this process. We report that cpg15 is expressed in the cat visual system at relatively high levels in the lateral geniculate nucleus (LGN) but at very low levels in its synaptic target, layer 4 of the visual cortex. Prenatally, when cpg15 mRNA in the LGN is most abundant, expression is insensitive to action potential blockade by tetrodotoxin. Postnatally, activity regulation of cpg15 emerges in the LGN coincident with development of ocular dominance columns in the visual cortex. cpg15 can be detected in layers 2/3 and 5/6 of visual cortex postnatally, and expression in layers 2/3 is activity-regulated during known periods of activity-dependent plasticity for these layers. Localization and regulation of cpg15 expression in the visual system are consistent with a presynaptic role for CPG15 in shaping dendritic arbors of target neurons during activity-dependent synaptic rearrangements, both in development and adulthood.

    View details for Web of Science ID 000082539900032

    View details for PubMedID 10479700

  • Retinal waves are governed by collective network properties JOURNAL OF NEUROSCIENCE Butts, D. A., Feller, M. B., Shatz, C. J., Rokhsar, D. S. 1999; 19 (9): 3580-3593

    Abstract

    Propagating neural activity in the developing mammalian retina is required for the normal patterning of retinothalamic connections. This activity exhibits a complex spatiotemporal pattern of initiation, propagation, and termination. Here, we discuss the behavior of a model of the developing retina using a combination of simulation and analytic calculation. Our model produces spatially and temporally restricted waves without requiring inhibition, consistent with the early depolarizing action of neurotransmitters in the retina. We find that highly correlated, temporally regular, and spatially restricted activity occurs over a range of network parameters; this ensures that such spatiotemporal patterns can be produced robustly by immature neural networks in which synaptic transmission by individual neurons may be unreliable. Wider variation of these parameters, however, results in several different regimes of wave behavior. We also present evidence that wave properties are locally determined by a single variable, the fraction of recruitable (i.e., nonrefractory) cells within the dendritic field of a retinal neuron. From this perspective, a given local area's ability to support waves with a wide range of propagation velocities-as observed in experiment-reflects the variability in the local state of excitability of that area. This prediction is supported by whole-cell voltage-clamp recordings, which measure significant wave-to-wave variability in the amount of synaptic input a cell receives when it participates in a wave. This approach to describing the developing retina provides unique insight into how the organization of a neural circuit can lead to the generation of complex correlated activity patterns.

    View details for Web of Science ID 000079883700031

    View details for PubMedID 10212317

  • Brain waves and brain wiring: The role of endogenous and sensory-driven neural activity in development PEDIATRIC RESEARCH Penn, A. A., Shatz, C. J. 1999; 45 (4): 447-458

    Abstract

    Neural activity is critical for sculpting the intricate circuits of the nervous system from initially imprecise neuronal connections. Disrupting the formation of these precise circuits may underlie many common neurodevelopmental disorders, ranging from subtle learning disorders to pervasive developmental delay. The necessity for sensory-driven activity has been widely recognized as crucial for infant brain development. Recent experiments in neurobiology now point to a similar requirement for endogenous neural activity generated by the nervous system itself before sensory input is available. Here we use the formation of precise neural circuits in the visual system to illustrate the principles of activity-dependent development. Competition between the projections from lateral geniculate nucleus neurons that receive sensory input from the two eyes shapes eye-specific connections from an initially diffuse projection into ocular dominance columns. When the competition is altered during a critical period for these changes, by depriving one eye of vision, the normal ocular dominance column pattern is disrupted. Before ocular dominance column formation, the highly ordered projection from retina to lateral geniculate nucleus develops. These connections form before the retina can respond to light, but at a time when retinal ganglion cells spontaneously generate highly correlated bursts of action potentials. Blockade of this endogenous activity, or biasing the competition in favor of one eye, results in a severe disruption of the pattern of retinogeniculate connections. Similar spontaneous, correlated activity has been identified in many locations in the developing central nervous system and is likely to be used during the formation of precise connections in many other neural systems. Understanding the processes of activity-dependent development could revolutionize our ability to identify, prevent, and treat developmental disorders resulting from disruptions of neural activity that interfere with the formation of precise neural circuits.

    View details for Web of Science ID 000079476200001

    View details for PubMedID 10203134

  • Establishment of patterned thalamocortical connections does not require nitric oxide synthase JOURNAL OF NEUROSCIENCE Finney, E. M., Shatz, C. J. 1998; 18 (21): 8826-8838

    Abstract

    Subplate neurons are early-generated neurons that project into the overlying neocortex and are required for the formation of ocular dominance columns. A subset of subplate neurons express nitric oxide synthase (NOS) and produce nitric oxide (NO), a neuronal messenger thought to be involved in adult hippocampal synaptic plasticity and also in the establishment of certain specific connections during visual system development. Here, we examine whether the NOS-containing subplate neurons are involved in ocular dominance column formation in the ferret visual system. Ocular dominance columns form in ferrets between postnatal day 35 (P35) and P60. NOS expression in the visual subplate is low at birth, increases to a maximum at the onset of ocular dominance column formation, and falls thereafter. Nevertheless, blockade of NOS with daily injections of nitroarginine from P14 to P56 fails to prevent the formation of ocular dominance columns, although NOS activity is reduced by >98%. To test further a requirement for NOS in the patterning of connections during CNS development, we examined the cortical barrels in the somatosensory system of mice carrying targeted disruptions of NOS that also received injections of nitroarginine; cortical barrels formed normally in these animals. In addition, barrel field plasticity induced by whisker ablation at birth was normal in nitroarginine-injected NOS knock-out mice. Thus, despite the dynamic regulation of NOS in subplate neurons, NO is unlikely to be essential for the patterning of thalamocortical connections either in visual or somatosensory systems.

    View details for Web of Science ID 000076616600027

    View details for PubMedID 9786989

  • Regulation of class I MHC gene expression in the developing and mature CNS by neural activity NEURON Corriveau, R. A., Huh, G. S., Shatz, C. J. 1998; 21 (3): 505-520

    Abstract

    To elucidate molecular mechanisms underlying activity-dependent synaptic remodeling in the developing mammalian visual system, we screened for genes whose expression in the lateral geniculate nucleus (LGN) is regulated by spontaneously generated action potentials present prior to vision. Activity blockade did not alter expression in the LGN of 32 known genes. Differential mRNA display, however, revealed a decrease in mRNAs encoding class I major histocompatibility complex antigens (class I MHC). Postnatally, visually driven activity can regulate class I MHC in the LGN during the final remodeling of retinal ganglion cell axon terminals. Moreover, in the mature hippocampus, class I MHC mRNA levels are increased by kainic acid-induced seizures. Normal expression of class I MHC mRNA is correlated with times and regions of synaptic plasticity, and immunohistochemistry confirms that class I MHC is present in specific subsets of CNS neurons. Finally, beta2-microglobulin, a cosubunit of class I MHC, and CD3zeta, a component of a receptor complex for class I MHC, are also expressed by CNS neurons. These observations indicate that class I MHC molecules, classically thought to mediate cell-cell interactions exclusively in immune function, may play a novel role in neuronal signaling and activity-dependent changes in synaptic connectivity.

    View details for Web of Science ID 000076196400008

    View details for PubMedID 9768838

  • Major glutamatergic projection from subplate into visual cortex during development JOURNAL OF COMPARATIVE NEUROLOGY Finney, E. M., Stone, J. R., Shatz, C. J. 1998; 398 (1): 105-118

    Abstract

    Subplate neurons, the first neurons of the cerebral cortex to differentiate and mature, are thought to be essential for the formation of connections between thalamus and cortex, such as the system of ocular dominance columns within layer 4 of visual cortex. To learn more about the requirement for subplate neurons in the formation of thalamocortical connections, we have sought to identify the neurotransmitters and peptides expressed by the specific class of subplate neurons that sends axonal projections into the overlying visual cortex. To label retrogradely subplate neurons, fluorescent latex microspheres were injected into primary visual cortex of postnatal day 28 ferrets, just prior to the onset of ocular dominance column formation. Subsequently, neurons were immunostained with antibodies against glutamate, glutamic acid decarboxylase (GAD-67), parvalbumin, neuropeptide Y (NPY), somatostatin (SRIF), or nitric oxide synthase (NOS). Retrograde labeling results indicate that the majority of subplate neurons projecting into the cortical plate reside in the upper half of the subplate. Combined immunostaining and microsphere labeling reveal that about half of cortically projecting subplate neurons are glutamatergic; most microsphere-labeled subplate neurons do not stain for GAD-67, parvalbumin, NPY, SRIF, or NOS. These observations suggest that subplate neurons can provide a significant glutamatergic synaptic input to the cortical plate, including the neurons of layer 4. If so, excitation from the axons of subplate neurons may be required in addition to that from lateral geniculate nucleus neurons for the activity-dependent synaptic interactions that lead to the formation of ocular dominance columns during development.

    View details for Web of Science ID 000075035900006

    View details for PubMedID 9703030

  • Activity-dependent cortical target selection by thalamic axons SCIENCE Catalano, S. M., Shatz, C. J. 1998; 281 (5376): 559-562

    Abstract

    Connections in the developing nervous system are thought to be formed initially by an activity-independent process of axon pathfinding and target selection and subsequently refined by neural activity. Blockade of sodium action potentials by intracranial infusion of tetrodotoxin in cats during the early period when axons from the lateral geniculate nucleus (LGN) were in the process of selecting visual cortex as their target altered the pattern and precision of this thalamocortical projection. The majority of LGN neurons, rather than projecting to visual cortex, elaborated a significant projection within the subplate of cortical areas normally bypassed. Those axons that did project to their correct target were topographically disorganized. Thus, neural activity is required for initial targeting decisions made by thalamic axons as they traverse the subplate.

    View details for Web of Science ID 000075012300040

    View details for PubMedID 9677198

  • Many major CNS axon projections develop normally in the absence of semaphorin III MOLECULAR AND CELLULAR NEUROSCIENCE Catalano, S. M., Messersmith, E. K., Goodman, C. S., Shatz, C. J., Chedotal, A. 1998; 11 (4): 173-182

    Abstract

    The semaphorins constitute a large gene family of transmembrane and secreted molecules, many of which are expressed in the nervous system. Genetic studies in Drosophila have revealed a role for semaphorins in axon guidance and synapse formation, and several in vitro studies in mice have demonstrated a dramatic chemorepellent effect of semaphorin III (Sema III) on the axons of several populations of neurons. To investigate the function of Sema III during in vivo axon guidance in the mammalian CNS, we studied the development of axonal projections in mutant mice lacking Sema III. Projections were studied for which either the in vitro evidence suggests a role for Sema III in axon guidance (e.g., cerebellar mossy fibers, thalamocortical axons, or cranial motor neurons) or the in vivo expression suggests a role for Sema III in axon guidance (e.g., cerebellar Purkinje cells, neocortex). We find that many major axonal projections, including climbing fiber, mossy fiber, thalamocortical, and basal forebrain projections and cranial nerves, develop normally in the absence of Sema III. Despite its in vitro function and in vivo expression, it appears as if Sema III is not absolutely required for the formation of many major CNS tracts. Such data are consistent with recent models suggesting that axon guidance is controlled by a balance of forces resulting from multiple guidance cues. Our data lead us to suggest that if Sema III functions in part to guide the formation of major axonal projections, then it does so in combination with both other semaphorins and other families of guidance molecules.

    View details for Web of Science ID 000075037700001

    View details for PubMedID 9675049

  • Competition in retinogeniculate patterning driven by spontaneous activity SCIENCE Penn, A. A., Riquelme, P. A., Feller, M. B., Shatz, C. J. 1998; 279 (5359): 2108-2112

    Abstract

    When contacts are first forming in the developing nervous system, many neurons generate spontaneous activity that has been hypothesized to shape appropriately patterned connections. In Mustela putorius furo, monocular intraocular blockade of spontaneous retinal waves of action potentials by cholinergic agents altered the subsequent eye-specific lamination pattern of the lateral geniculate nucleus (LGN). The projection from the active retina was greatly expanded into territory normally belonging to the other eye, and the projection from the inactive retina was substantially reduced. Thus, interocular competition driven by endogenous retinal activity determines the pattern of eye-specific connections from retina to LGN, demonstrating that spontaneous activity can produce highly stereotyped patterns of connections before the onset of visual experience.

    View details for Web of Science ID 000072775600048

    View details for PubMedID 9516112

  • A two-layer model describes the spatiotemporal properties of spontaneous retinal waves COMPUTATIONAL NEUROSCIENCE: TRENDS IN RESEARCH Butts, D. A., Feller, M. B., Aaron, H. L., Shatz, C. J., Rokhsar, D. S. 1998: 337-342
  • Activity-dependent regulation of NMDAR1 immunoreactivity in the developing visual cortex JOURNAL OF NEUROSCIENCE Catalano, S. M., Chang, C. K., Shatz, C. J. 1997; 17 (21): 8376-8390

    Abstract

    NMDA receptors have been implicated in activity-dependent synaptic plasticity in the developing visual cortex. We examined the distribution of immunocytochemically detectable NMDAR1 in visual cortex of cats and ferrets from late embryonic ages to adulthood. Cortical neurons are initially highly immunostained. This level declines gradually over development, with the notable exception of cortical layers 2/3, where levels of NMDAR1 immunostaining remain high into adulthood. Within layer 4, the decline in NMDAR1 immunostaining to adult levels coincides with the completion of ocular dominance column formation and the end of the critical period for layer 4. To determine whether NMDAR1 immunoreactivity is regulated by retinal activity, animals were dark-reared or retinal activity was completely blocked in one eye with tetrodotoxin (TTX). Dark-rearing does not cause detectable changes in NMDAR1 immunoreactivity. However, 2 weeks of monocular TTX administration decreases NMDAR1 immunoreactivity in layer 4 of the columns of the blocked eye. Thus, high levels of NMDAR1 immunostaining within the visual cortex are temporally correlated with ocular dominance column formation and developmental plasticity; the persistence of staining in layers 2/3 also correlates with the physiological plasticity present in these layers in the adult. In addition, visual experience is not required for the developmental changes in the laminar pattern of NMDAR1 levels, but the presence of high levels of NMDAR1 in layer 4 during the critical period does require retinal activity. These observations are consistent with a central role for NMDA receptors in promoting and ultimately limiting synaptic rearrangements in the developing neocortex.

    View details for Web of Science ID A1997YC94700030

    View details for PubMedID 9334411

  • Dynamic processes shape spatiotemporal properties of retinal waves NEURON Feller, M. B., Butts, D. A., Aaron, H. L., Rokhsar, D. S., Shatz, C. J. 1997; 19 (2): 293-306

    Abstract

    In the developing mammalian retina, spontaneous waves of action potentials are present in the ganglion cell layer weeks before vision. These waves are known to be generated by a synaptically connected network of amacrine cells and retinal ganglion cells, and exhibit complex spatiotemporal patterns, characterized by shifting domains of coactivation. Here, we present a novel dynamical model consisting of two coupled populations of cells that quantitatively reproduces the experimentally observed domain sizes, interwave intervals, and wavefront velocity profiles. Model and experiment together show that the highly correlated activity generated by retinal waves can be explained by a combination of random spontaneous activation of cells and the past history of local retinal activity.

    View details for Web of Science ID A1997XU14600009

    View details for PubMedID 9292720

  • Blockade of endogenous ligands of trkB inhibits formation of ocular dominance columns NEURON CABELLI, R. J., Shelton, D. L., Segal, R. A., Shatz, C. J. 1997; 19 (1): 63-76

    Abstract

    We have examined the hypothesis that the segregation of LGN axon terminals into ocular dominance (OD) patches in layer 4 of the visual cortex requires neurotrophins, acting as signals to modulate the pattern of synaptic connectivity. Neurotrophin receptor antagonists, composed of the extracellular domain of each member of the trk family of neurotrophin receptors fused to a human Fc domain, were infused directly into visual cortex during the peak phase of OD column formation. Infusion of trkB-IgG, which binds BDNF and NT-4/5, inhibited the formation of OD patches within layer 4, while trkA-IgG and trkC-IgG, which preferentially bind NGF and NT-3, respectively, had no effect. The autoradiographic labeling of LGN terminals in cortical layer 4 was reduced by trkB-IgG, in contrast with the increased labeling observed following NT-4/5 infusion. These data suggest that an endogenous ligand of trkB, normally present in limiting amounts within visual cortex, is necessary for the selective growth and remodeling of LGN axons into eye-specific patches.

    View details for Web of Science ID A1997XN39400007

    View details for PubMedID 9247264

  • Dendritic development of retinal ganglion cells after prenatal intracranial infusion of tetrodotoxin VISUAL NEUROSCIENCE Campbell, G., Ramoa, A. S., Stryker, M. P., Shatz, C. J. 1997; 14 (4): 779-788

    Abstract

    The dendritic form of a cell may be established by many factors both intrinsic and environmental. Blockade of action potentials along the course of axons and in their postsynaptic targets dramatically alters the development of axonal morphology. The extent to which blockade of target cell activity retrogradely alters the dendritic morphology of the presynaptic cells is unknown. To determine whether the establishment of dendritic form by developing retinal ganglion cells depends on activity within their targets, the sodium channel blocker, tetrodotoxin (TTX), was administered via minipumps to the diencephalon of cat fetuses from embryonic day 43 (E43) to E57. At E57 retinae were removed and living retinal ganglion cells injected in vitro with Lucifer yellow to reveal their dendritic morphology. In the TTX-treated animals both alpha and beta types of retinal ganglion cells were present, as were putative gamma cells. Overall, the dendrites of retinal ganglion cells in TTX-treated animals appeared qualitatively and quantitatively similar to those of untreated animals. The only significant change in the TTX-treated cases was a small increase in the number of dendritic spines on the non-beta cells. These results indicate that the acquisition of basic dendritic form of developing ganglion cells is not influenced by the action potential activity within their targets, and that it is also independent of the terminal branching patterns of their axons.

    View details for Web of Science ID A1997XJ33500016

    View details for PubMedID 9279005

  • Migration of neocortical neurons in the absence of functional NMDA receptors MOLECULAR AND CELLULAR NEUROSCIENCE Messersmith, E. K., Feller, M. B., Zhang, H., Shatz, C. J. 1997; 9 (5-6): 347-357

    Abstract

    A variety of factors, from cell adhesion to changes in intracellular calcium, are thought to influence neuronal migration. Here we examine the possibility that calcium influx mediated via NMDA receptors regulates migration of neocortical neurons. We have examined the cytoarchitecture of the cortex in transgenic mice lacking functional NMDA receptors. Using cell birthdating techniques we found that cells in the developing neocortex of NMDAR-1 mutant mice have a distribution indistinguishable from that in animals with functional NMDA receptors, implying normal rates and routes of migration. These observations contrast with previous in vitro pharmacological studies of cerebellar granule cell migration, in which a role for NMDA receptors has been demonstrated. Thus, either different mechanisms are responsible for controlling neuronal migration in neocortex versus cerebellum or, more likely, neocortical neurons in NMDAR-1 mutant mice have acquired compensatory mechanisms for cell migration.

    View details for Web of Science ID A1997YD34400003

    View details for PubMedID 9361273

  • Form from function in visual system development. Harvey lectures Shatz, C. J. 1997; 93: 17-34

    View details for PubMedID 10941416

  • Changing patterns of expression and subcellular localization of trkB in the developing visual system JOURNAL OF NEUROSCIENCE CABELLI, R. J., Allendoerfer, K. L., Radeke, M. J., Welcher, A. A., Feinstein, S. C., Shatz, C. J. 1996; 16 (24): 7965-7980

    Abstract

    Neurotrophins play important roles in the survival, differentiation, and maintenance of CNS neurons. To begin to investigate specific roles for these factors in the mammalian visual system, we have examined the cellular localization of the neurotrophin receptor trkB within the developing cerebral cortex and thalamus of the ferret using extracellular domain-specific antibodies. At prenatal ages (gestation is 41 d), trkB-immunostained fibers were observed in the internal capsule and as two distinct fascicles within the intermediate zone of the cerebral cortex. The staining of these fiber tracts declined with increasing age, whereas soma and dendrite staining of cortical neurons was first evident in early postnatal life and increased during subsequent development. Staining of subplate neurons [by prenatal day 5 (P5)] was followed by staining of cortical layer 5 neurons (at P10). By P31, trkB immunoreactivity was particularly prominent in layers 3 and 5 but was absent from subplate neurons. Staining included cells, especially pyramidal neurons, in all cortical layers by P45, and this pattern was maintained into adulthood. The optic tract and fibers within the lateral geniculate nucleus (LGN) were also strongly trkB immunoreactive at prenatal ages. Cellular staining of a subset of LGN neurons, those within the C-layers and perigeniculate nucleus, was apparent by P10 and maintained until P45, when the adult pattern of highly trkB-immunoreactive neurons in all layers of the LGN first appeared. The pattern of trkB immunoreactivity suggests that specific subsets of cortical and thalamic neurons may respond to neurotrophins such as brain-derived neurotrophic factor and/or NT-4/5 at discrete developmental times and locations. The appearance of trkB on axon fibers early in development and then on cell bodies and dendritic processes later is consistent with roles for both long-range and local, including autocrine and/or paracrine, delivery of neurotrophins in cell survival and maturation.

    View details for Web of Science ID A1996VW94500018

    View details for PubMedID 8987824

  • Synaptic activity and the construction of cortical circuits SCIENCE Katz, L. C., Shatz, C. J. 1996; 274 (5290): 1133-1138

    Abstract

    Vision is critical for the functional and structural maturation of connections in the mammalian visual system. Visual experience, however, is a subset of a more general requirement for neural activity in transforming immature circuits into the organized connections that subserve adult brain function. Early in development, internally generated spontaneous activity sculpts circuits on the basis of the brain's "best guess" at the initial configuration of connections necessary for function and survival. With maturation of the sense organs, the developing brain relies less on spontaneous activity and increasingly on sensory experience. The sequential combination of spontaneously generated and experience-dependent neural activity endows the brain with an ongoing ability to accommodate to dynamically changing inputs during development and throughout life.

    View details for Web of Science ID A1996VT33500032

    View details for PubMedID 8895456

  • Thalamic relay of spontaneous retinal activity prior to vision NEURON Mooney, R., Penn, A. A., Gallego, R., Shatz, C. J. 1996; 17 (5): 863-874

    Abstract

    Before vision, retinal ganglion cells produce spontaneous waves of action potentials. A crucial question is whether this spontaneous activity is transmitted to lateral geniculate nucleus (LGN) neurons. Using a novel in vitro preparation, we report that LGN neurons receive periodic barrages of postsynaptic currents from the retina that drive them to fire bursts of action potentials. Groups of LGN neurons are highly correlated in their firing. Experiments in wild-type and NMDAR1 knockout mice show that NMDA receptor activation is not necessary for firing. The transmission of the highly correlated retinal activity to the LGN supports the hypothesis that retinal waves drive retinogeniculate synaptic remodeling. Because LGN neurons are driven to fire action potentials, this spontaneous activity could also act more centrally to influence synaptic modification within the developing visual cortex.

    View details for Web of Science ID A1996VV15100009

    View details for PubMedID 8938119

  • Developmental changes revealed by immunohistochemical markers in human cerebral cortex CEREBRAL CORTEX Honig, L. S., Herrmann, K., Shatz, C. J. 1996; 6 (6): 794-806

    Abstract

    The developing human cerebral cortex is distinguished by a particularly wide subplate, a transient zone in which crucial cell-cell interactions occur. To further understand the role of the subplate in human brain development, we have studied the immunohistochemical expression of certain neuronal (GAP-43, MAP-2, parvalbumin) and astroglial (vimentin, GFAP) markers in the developing visual cortex from gestational ages of 14 weeks to 9 months post-term. At 14-22 weeks, immunoreactivity to GAP-43, a protein involved in axonal outgrowth, was most prominent in the subplate and marginal zone neuropil and in the fibers of the radiations running near the ventricular zone; at 22-42 weeks, GAP-43 immunoreactive fibers were observed in the maturing cortical plate. Immunoreactivity for the microtubule-associated protein MAP-2 was present in the differentiating cortical plate at 14 weeks, but at 22-42 weeks was most prominent in the somata and dendrites of differentiated neurons, particularly the Cajal-Retzius neurons of the marginal zone, in neurons of the subplate and in those forming cortical layer 5. Parvalbumin immunoreactivity did not appear until 26 weeks, when stained neurons were in a sparse band of cells in layer 6 and upper subplate. Vimentin and GFAP did not stain differentiated neuronal cells. Vimentin immunoreactivity appeared early in neuroepithelial and radial glial cells, decreasing after 35 weeks, with a concomitant increase in GFAP immunoreactivity in radial glial and maturing astrocytic cells. Our results show that despite the greater complexity of the developing human neocortex, molecular markers are expressed in spatial and temporal patterns similar to those observed in non-human primates, carnivores and rodents. These protein markers should prove useful in developmental staging, and in providing a framework in which to examine congenital disorders of cerebral development.

    View details for Web of Science ID A1996VL76400006

    View details for PubMedID 8922336

  • Requirement for cholinergic synaptic transmission in the propagation of spontaneous retinal waves SCIENCE Feller, M. B., WELLIS, D. P., Stellwagen, D., Werblin, F. S., Shatz, C. J. 1996; 272 (5265): 1182-1187

    Abstract

    Highly correlated neural activity in the form of spontaneous waves of action potentials is present in the developing retina weeks before vision. Optical imaging revealed that these waves consist of spatially restricted domains of activity that form a mosaic pattern over the entire retinal ganglion cell layer. Whole-cell recordings indicate that wave generation requires synaptic activation of neuronal nicotinic acetylcholine receptors on ganglion cells. The only cholinergic cells in these immature retinas are a uniformly distributed bistratified population of amacrine cells, as assessed by antibodies to choline acetyltransferase. The results indicate that the major source of synaptic input to retinal ganglion cells is a system of cholinergic amacrine cells, whose activity is required for wave propagation in the developing retina.

    View details for Web of Science ID A1996UM88900054

    View details for PubMedID 8638165

  • Emergence of order in visual system development (Reprinted from Proc Natl Acad Sci USA, vol 93, pg 602-608, 1996) JOURNAL OF PHYSIOLOGY-PARIS Shatz, C. J. 1996; 90 (3-4): 141-150

    Abstract

    Neural connections in the adult central nervous system are highly precise. In the visual system, retinal ganglion cells send their axons to target neurons in the lateral geniculate nucleus (LGN) in such a way that axons originating from the two eyes terminate in adjacent but non-overlapping eye-specific layers. During development, however, inputs from the two eyes are intermixed, and the adult pattern emerges gradually as axons from the two eyes sort out to form the layers. Experiments indicate that the sorting out process, even though it occurs in utero in higher mammals and always before vision, requires retinal ganglion cell signaling: blocking retinal ganglion cell action potentials with tetrodotoxin prevents the formation of the layers. These action potentials are endogenously generated by the ganglion cells, which fire spontaneously and synchronously with each other, generating 'waves' of activity that travel across the retina. Calcium imaging of the retina shows that the ganglion cells undergo correlated calcium bursting to generate the waves, and that amacrine cells also participate in the correlated activity patterns. Physiological recordings from LGN neurons in vitro indicate that the quasi-periodic activity generated by the retinal ganglion cells is transmitted across the synapse between ganglion cells to drive target LGN neurons. These observations suggest that: 1) a neural circuit within the immature retina is responsible for generating specific spatiotemporal patterns of neural activity: 2) spontaneous activity generated in the retina is propagated across central synapses; and 3) even before the photoreceptors are present, nerve cell function is essential for correct wiring of the visual system during early development. Since spontaneously generated activity is known to be present elsewhere in the developing central nervous system (CNS), this process of activity-dependent wiring could be used throughout the nervous system to help refine early sets of neural connections into their highly precise adult patterns.

    View details for Web of Science ID A1996WN39500002

    View details for PubMedID 9116657

  • BLOCKADE OF ACTION-POTENTIAL ACTIVITY ALTERS INITIAL ARBORIZATION OF THALAMIC AXONS WITHIN CORTICAL LAYER-4 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Herrmann, K., Shatz, C. J. 1995; 92 (24): 11244-11248

    Abstract

    In the formation of connections during the development of the nervous system, it is generally accepted that there is an early phase not requiring neural activity and a later activity-dependent phase. The initial processes of axonal pathfinding and target selection are not thought to require neural activity, whereas the later fine-tuning of connections into their final adult patterns does. We report an apparent exception to this rule in which action potential activity seems to be required very early in development for thalamic axons to form appropriate patterns of terminal arborizations with their ultimate target neurons in layer 4 of the cerebral cortex. Blockade of sodium action potentials during the 2-week fetal period when visual thalamic axons initially grow into the primary visual cortex in cats prevents the normally occurring branching of lateral geniculate nucleus axons within layer 4. This observation implies a role for action-potential activity in cerebral cortical development far earlier than previously suspected, weeks before eye-opening and the onset of the well-known process of activity-dependent reorganization of axonal terminal arbors that leads to the formation of ocular dominance columns.

    View details for Web of Science ID A1995TF89100087

    View details for PubMedID 7479973

  • SEMAPHORIN-III CAN FUNCTION AS A SELECTIVE CHEMOREPELLENT TO PATTERN SENSORY PROJECTIONS IN THE SPINAL-CORD NEURON Messersmith, E. K., Leonardo, E. D., Shatz, C. J., TESSIERLAVIGNE, M., Goodman, C. S., Kolodkin, A. L. 1995; 14 (5): 949-959

    Abstract

    Distinct classes of primary sensory neurons in dorsal root ganglia subserve different sensory modalities, terminate in different dorsoventral locations in the spinal cord, and display different neurotrophin response profiles. Large diameter muscle afferents that terminate in the ventral spinal cord are NT-3 responsive, whereas small diameter afferents subserving pain and temperature are NGF responsive and terminate in the dorsal spinal cord. Previous in vitro studies showed that the developing ventral spinal cord secretes a diffusible factor that inhibits the growth of sensory axons. Here we show that this factor repels NGF-responsive axons but has little effect on NT-3-responsive axons. We also provide evidence implicating semaphorin III/collapsin, a diffusible guidance molecule expressed by ventral spinal cord cells, in mediating this effect. These results suggest that semaphorin III functions to pattern sensory projections by selectively repelling axons that normally terminate dorsally.

    View details for Web of Science ID A1995QY93500007

    View details for PubMedID 7748562

  • EARLY FUNCTIONAL NEURAL NETWORKS IN THE DEVELOPING RETINA NATURE Wong, R. O., CHERNJAVSKY, A., Smith, S. J., Shatz, C. J. 1995; 374 (6524): 716-718

    Abstract

    In the adult mammalian retina, the principal direction of information flow is along a vertical pathway from photoreceptors to retinal interneurons to ganglion cells, the output neurons of the retina. We report here, however, that initially in development, at a time when the photoreceptors are not yet even present, there are already functionally defined networks within the retina. These networks are spontaneously active rather than visually driven, and they involve horizontal rather than vertical pathways. By means of optical recording using the calcium-sensitive dye Fura-2, we have found that sets of retinal ganglion cells and amacrine cells, a type of retinal interneuron, undergo synchronized oscillations in intracellular calcium concentration. These oscillations are highly correlated among subgroups of neighbouring cells, and spread in a wave-like fashion tangentially across the retina. Thus, in development of retinal circuitry, the initial patterning of neuronal function occurs in the horizontal domain before the adult pattern of vertical information transfer emerges.

    View details for Web of Science ID A1995QU30400048

    View details for PubMedID 7715725

  • INHIBITION OF OCULAR DOMINANCE COLUMN FORMATION BY INFUSION OF NT-4/5 OR BDNF SCIENCE CABELLI, R. J., Hohn, A., Shatz, C. J. 1995; 267 (5204): 1662-1666

    Abstract

    During the development of the visual system of higher mammals, axons from the lateral geniculate nucleus (LGN) become segregated into eye-specific patches (the ocular dominance columns) within their target, layer 4 of the primary visual cortex. This occurs as a consequence of activity-dependent synaptic competition between axons representing the two eyes. The possibility that this competition could be mediated through neurotrophin-receptor interactions was tested. Infusion of neurotrophin-4/5 (NT-4/5) or brain-derived neurotrophic factor (BDNF) into cat primary visual cortex inhibited column formation within the immediate vicinity of the infusion site but not elsewhere in the visual cortex. Infusion of nerve growth factor, neurotrophin 3 (NT-3), or vehicle solution did not affect column formation. These observations implicate TrkB, the common receptor for BDNF and NT-4/5, in the segregation of LGN axons into ocular dominance columns in layer 4. Moreover, they suggest that in addition to their better known roles in the prevention of cell death, neurotrophins may also mediate the activity-dependent control of axonal branching during development of the central nervous system.

    View details for Web of Science ID A1995QM39700042

    View details for PubMedID 7886458

  • ULTRASTRUCTURAL EVIDENCE FOR SYNAPTIC-INTERACTIONS BETWEEN THALAMOCORTICAL AXONS AND SUBPLATE NEURONS EUROPEAN JOURNAL OF NEUROSCIENCE Herrmann, K., Antonini, A., Shatz, C. J. 1994; 6 (11): 1729-1742

    Abstract

    Thalamic axons are known to accumulate in the subplate for a protracted period prior to invading the cortical plate and contacting their ultimate targets, the neurons of layer 4. We have examined the synaptic contacts made by visual and somatosensory thalamic axons during the transition period in which axons begin to leave the subplate and invade the cortical plate in the ferret. We first determined when geniculocortical axons leave the subplate and begin to grow into layer 4 of the visual cortex by injecting 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine (Dil) into the lateral geniculate nucleus (LGN). By birth most LGN axons are still confined to the subplate. Over the next 10 days LGN axons grow into layer 4, but many axons retain axonal branches within the subplate. To establish whether thalamic axons make synaptic contacts within the subplate, the anterograde tracer PHA-L was injected into thalamic nuclei of neonatal ferrets between postnatal day 3 and 12 to label thalamic axons at the electron microscope level. The analysis of the PHA-L injections confirmed the Dil data regarding the timing of ingrowth of thalamic axons into the cortical plate. At the electron microscope level, PHA-L-labelled axons were found to form synaptic contacts in the subplate. The thalamic axon terminals were presynaptic primarily to dendritic shafts and dendritic spines. Between postnatal days 12 and 20 labelled synapses were also observed within layer 4 of the cortex. The ultrastructural appearance of the synapses did not differ significantly in the subplate and cortical plate, with regard to type of postsynaptic profiles, length of postsynaptic density or presynaptic terminal size. These observations provide direct evidence that thalamocortical axons make synaptic contacts with subplate neurons, the only cell type within the subplate possessing mature dendrites and dendritic spines; they also suggest that functional interactions between thalamic axons and subplate neurons could play a role in the establishment of appropriate thalamocortical connections.

    View details for Web of Science ID A1994PR42300010

    View details for PubMedID 7874312

  • Viktor Hamburger Award review. Role for spontaneous neural activity in the patterning of connections between retina and LGN during visual system development. International journal of developmental neuroscience Shatz, C. J. 1994; 12 (6): 531-546

    View details for PubMedID 7892783

  • SEGREGATION OF GENICULOCORTICAL AFFERENTS DURING THE CRITICAL PERIOD - A ROLE FOR SUBPLATE NEURONS JOURNAL OF NEUROSCIENCE Ghosh, A., Shatz, C. J. 1994; 14 (6): 3862-3880

    Abstract

    To investigate the cellular interactions within the mammalian visual cortex that are important in ocular dominance column formation, we have examined the role of subplate neurons in this process. LGN axons segregate in layer 4 of the cat's visual cortex between the third and sixth postnatal weeks to give rise to the adult pattern of ocular dominance columns. Subplate neurons are a transient population of neurons that sit in the white matter but have extensive projections into the overlying cortex, particularly layer 4, during neonatal life. Many subplate neurons are present at birth, but most are gone by the end of the period of LGN axon segregation. To examine whether these neurons are required for the segregation of LGN axons, we deleted them by intracortical injections of kainic acid either just after LGN axons had grown into layer 4 (first postnatal week) or later, just before the onset of segregation (third postnatal week). The consequences for the patterning of geniculocortical terminals were evaluated by transneuronal transport of 3H-proline injected into one eye at times when segregation would normally be complete. Following deletion of subplate neurons at either age, LGN axons failed to segregate into ocular dominance columns. Following the late deletions only, geniculocortical axons lost their laminar restriction to layer 4 and projected to layers 2 and 3 as well. Deletion of subplate neurons also resulted in long-term changes in the cytoarchitecture of layer 4. These observations suggest that the interactions that mediate segregation of LGN axons within layer 4 of visual cortex are susceptible to influences from subplate neurons. Although the mechanisms by which subplate neurons exert their effect are not yet clear, these experiments strongly suggest that interactions between LGN axons and layer 4 neurons are not sufficient for column formation, and that subplate neurons most likely play a critical role in interactions leading to ocular segregation.

    View details for Web of Science ID A1994NR13800038

    View details for PubMedID 8207493

  • NEURONAL COUPLING IN THE DEVELOPING MAMMALIAN RETINA JOURNAL OF NEUROSCIENCE Penn, A. A., Wong, R. O., Shatz, C. J. 1994; 14 (6): 3805-3815

    Abstract

    During the first 3 weeks of postnatal development in the ferret retina, cells in the ganglion cell layer spontaneously generate waves of electrical activity that travel across the retina in the absence of mature photoreceptors (Meister et al., 1991; Wong et al., 1993). Since few chemical synapses are present at the earliest stages when waves are present, we have explored whether gap junctions could act to correlate the activity of cells in the immature ganglion cell layer. Retinal ganglion cells in a living in vitro preparation from postnatal day 1 (P1) to P45 were intracellularly injected with the tracer Neurobiotin and the fluorescent dye Lucifer yellow, molecules that are known to pass through gap junctions. Lucifer yellow consistently filled only the injected cell, whereas Neurobiotin filled not only the injected cell but also passed to a constellation of neighboring cells. Coupling revealed by Neurobiotin is seen as early as P1, but, at this stage, it was not possible to identify the various morphological types of cells that were coupled. Thereafter, alpha ganglion cells showed homologous coupling to other alpha cells and to both conventionally placed and displaced amacrine cells. Likewise, gamma ganglion cells appeared coupled to other gamma cells and to amacrine cells. However, beta ganglion cells never showed tracer coupling in the neonatal or in adult retinas. The percentage of alpha and gamma cells that were coupled to other cells increased progressively with age. By the end of the third postnatal week, the pattern of Neurobiotin coupling in the ferret retina was adult-like, with virtually every injected alpha cell showing tracer coupling. Our observations suggest that intercellular junctions able to pass Neurobiotin are present in the inner plexiform layer during the period when the firing of retinal ganglion cells is highly correlated. Such junctions could contribute to synchronization of the activity of subsets of neighboring ganglion cells during development, but it cannot be the sole mediator of this activity because beta cells, which also participate in the correlated activity, showed no coupling at any stage. In addition, the continued presence of coupling in the adult retina implies that other changes in retinal circuitry are likely to contribute to the disappearance of the waves.

    View details for Web of Science ID A1994NR13800033

    View details for PubMedID 8207489

  • INDEPENDENT CONTROL OF DENDRITIC AND AXONAL FORM IN THE DEVELOPING LATERAL GENICULATE-NUCLEUS JOURNAL OF NEUROSCIENCE Dalva, M. B., Ghosh, A., Shatz, C. J. 1994; 14 (6): 3588-3602

    Abstract

    To identify mechanisms that regulate neuronal form in the mammalian CNS, we have examined dendritic development in the lateral geniculate nucleus (LGN) during the period of segregation of retinal ganglion cell axons. The tracer Dil was used to label retrogradely LGN neurons that send their axons to primary visual cortex at different ages between embryonic day 36 (E36) and E60 in the cat. LGN neurons grow extensively during this period, in concert with the progressive restriction of ganglion cell axons from the two eyes to their appropriate eye-specific layers. At E36 neurons have simple bipolar morphology; by E60 all have acquired complex multipolar dendritic trees. During this period, soma size increases by 190% and total dendritic length increases 240%. Dendritic complexity, as measured by dendritic branch points, also increases. As dendrites grow, the number of spines increases, but their density remains constant at 0.015/micron throughout this period. Since it is known that blockade of action potential activity significantly alters the branching pattern and extent of retinal ganglion cell axonal arbors within the LGN, we also investigated whether the dendritic development of the postsynaptic LGN neurons is similarly susceptible. Following 2 weeks of the intracranial minipump infusion of TTX between E42 and E56, the morphology of LGN neurons was examined. Surprisingly in view of the striking effect of the treatment on the morphology of retinal ganglion cell axons, dendritic growth and development were essentially normal. However, the density of dendritic spines increased almost threefold, suggesting that this specific feature of dendritic morphology is highly regulated by action potential activity. These observations indicate that normally during this period of development, the previously described changes that occur in the morphology of the presynaptic inputs to LGN neurons are accompanied by a progressive growth of post-synaptic dendrites. Because the intracranial TTX infusions have almost certainly blocked all sodium action potentials, our results suggest that the basic dendritic framework of LGN neurons can be achieved even in the absence of this form of neural activity. Moreover, since the same treatment causes a profound change in the morphology of the presynaptic axons, at least some aspects of axonal and dendritic form must be controlled independently during this prenatal period of development.

    View details for Web of Science ID A1994NR13800016

    View details for PubMedID 8207474

  • SUBPLATE PIONEERS AND THE FORMATION OF DESCENDING CONNECTIONS FROM CEREBRAL-CORTEX JOURNAL OF NEUROSCIENCE McConnell, S. K., Ghosh, A., Shatz, C. J. 1994; 14 (4): 1892-1907

    Abstract

    The adult cerebral cortex extends axons to a variety of subcortical targets, including the thalamus and superior colliculus. These descending projections are pioneered during development by the axons of a transient population of subplate neurons (McConnell et al., 1989). We show here that the descending axons of cortical plate neurons appear to be delayed significantly in their outgrowth, compared with those of subplate neurons. To assess the possible role of subplate neurons in the formation of these pathways, subplate neurons were ablated during the embryonic period. In all cases, an axon pathway formed from visual cortex through the internal capsule and into the thalamus. In half of all cases, however, cortical axons failed to invade their normal subcortical targets. In the other half, targets were innervated normally. Subplate neurons are therefore likely to provide important cues that aid the process by which cortical axons grow toward, select, and invade their subcortical targets.

    View details for Web of Science ID A1994NF02600002

    View details for PubMedID 7512631

  • REGULATION OF NEUROTROPHIN RECEPTORS DURING THE MATURATION OF THE MAMMALIAN VISUAL-SYSTEM JOURNAL OF NEUROSCIENCE Allendoerfer, K. L., CABELLI, R. J., Escandon, E., Kaplan, D. R., Nikolics, K., Shatz, C. J. 1994; 14 (3): 1795-1811

    Abstract

    Cell division, cell death, and remodeling of connections are major features of the construction of the mammalian CNS. We have begun to address the role of neurotrophins in these events through characterization of the expression of their receptors in the developing ferret visual system. By use of chemical cross-linking of iodinated neurotrophins, proteins corresponding to trkB, trkC, and p75 were identified as receptors for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) throughout development. BDNF was also cross-linked to a truncated form of trkB that lacks the tyrosine kinase domain (trkB. T1) in retinal target tissues and in cortex. At the earliest developmental age examined (E24), the ratio of full-length to truncated trkB is > > 1 in the retinal target tissues, LGN and superior colliculus. During the ensuing period of retinal ganglion cell death and segregation into eye-specific layers, the amount of truncated trkB increases markedly relative to full-length trkB. By P27, truncated trkB is the predominant receptor for BDNF in the retinal target tissues and this pattern is maintained into adulthood. Within all subdivisions of visual cortex including the ventricular zone (VZ), intermediate zone (IZ), and cortical plate (CP), similar profiles of bands are observed. The developmental increase in abundance of truncated trkB relative to full-length occurs earliest in the VZ, with a major increase between E30 and P3. In the IZ, this shift to a predominance of truncated trkB occurs between P15 and P30, while in the CP the shift is even further delayed, not occurring until after P30. Within each subdivision of cortex, the shift to a predominance of truncated trkB occurs at times that correlate with the onset of cell death and maturation of axonal connections. This study demonstrates that members of the trk family, previously identified in the CNS on the basis of mRNA transcripts, are present as receptors with specific binding affinities for BDNF and NT-3. Moreover, the correspondence between the developmental shift from full-length to truncated trkB and the critical periods for cell fate determination, cell death, and axonal remodeling suggests an important role for neurotrophic factors in the development of the visual system.

    View details for Web of Science ID A1994MZ40700037

    View details for PubMedID 8126572

  • THE SUBPLATE, A TRANSIENT NEOCORTICAL STRUCTURE - ITS ROLE IN THE DEVELOPMENT OF CONNECTIONS BETWEEN THALAMUS AND CORTEX ANNUAL REVIEW OF NEUROSCIENCE Allendoerfer, K. L., Shatz, C. J. 1994; 17: 185-218

    View details for Web of Science ID A1994NA54400006

    View details for PubMedID 8210173

  • TRANSIENT PERIOD OF CORRELATED BURSTING ACTIVITY DURING DEVELOPMENT OF THE MAMMALIAN RETINA NEURON Wong, R. O., Meister, M., Shatz, C. J. 1993; 11 (5): 923-938

    Abstract

    The refinement of early connections in the visual pathway requires electrical activity in the retina before the onset of vision. Using a multielectrode array, we have shown that the spontaneous activity of cells in the neonatal ferret retina is correlated by patterns of periodically generated traveling waves. Here, we examine developmental changes in the characteristics of the waves and show that retinal ganglion cells participate in these patterns of activity, which are seen during the same period as synaptic modification in the lateral geniculate nucleus; that the waves subside gradually as the connectivity in the lateral geniculate nucleus stabilizes; and that their spatial structure allows for refinement of the retinotopic map, as well as for eye-specific segregation in the lateral geniculate nucleus.

    View details for Web of Science ID A1993MJ04100014

    View details for PubMedID 8240814

  • ENHANCEMENT OF TRANSMISSION AT THE DEVELOPING RETINOGENICULATE SYNAPSE NEURON Mooney, R., Madison, D. V., Shatz, C. J. 1993; 10 (5): 815-825

    Abstract

    Axon terminals from retinal ganglion cells in the left and right eyes initially overlap with each other in the lateral geniculate nucleus of the neonatal ferret, then segregate into eye-specific layers via an activity-dependent process. Brain slices were used to show that, during this period of reorganization, retinal terminals within the lateral geniculate nucleus evoke excitatory postsynaptic currents composed of both NMDA and non-NMDA receptor-mediated currents. The amplitude of these currents could be enhanced for several tens of minutes to more than an hour by several bursts of high frequency synaptic stimulation, and the induction of enhancement appears to depend on NMDA receptor activation. Synaptic enhancement such as this could provide one of the physiological mechanisms by which retinal terminals segregate into eye-specific layers during development.

    View details for Web of Science ID A1993LD32200005

    View details for PubMedID 8388224

  • REPAIR AND REPLACEMENT TO RESTORE SIGHT - REPORT FROM THE PANEL ON GANGLION-CELL CONNECTIVITY ARCHIVES OF OPHTHALMOLOGY Shatz, C. J., OLEARY, D. D. 1993; 111 (4): 472-477

    View details for Web of Science ID A1993KW76700025

    View details for PubMedID 8470976

  • A ROLE FOR SUBPLATE NEURONS IN THE PATTERNING OF CONNECTIONS FROM THALAMUS TO NEOCORTEX DEVELOPMENT Ghosh, A., Shatz, C. J. 1993; 117 (3): 1031-1047

    Abstract

    During cerebral cortical development, ingrowing axons from different thalamic nuclei select and invade their cortical targets. The selection of an appropriate target is first evident even before thalamic axons grow into the cortical plate: initially axons accumulate and wait below their cortical target area in a zone called the subplate. This zone also contains the first postmitotic neurons of the cerebral cortex, the subplate neurons. Here we have investigated whether subplate neurons are involved in the process of target selection by thalamic axons by ablating them from specific cortical regions at the onset of the waiting period and examining the subsequent thalamocortical axon projection patterns. Subplate neurons were ablated at the onset of the waiting period by intracortical injections of kainic acid. The effect of the ablation on the thalamocortical projection from visual thalamus was examined by DiI-labeling of the LGN days to weeks following the lesion. At two to four weeks post-lesion, times when LGN axons would have normally invaded the cortical plate, the axons remained below the cortical plate and grew past their appropriate cortical target in an anomalous pathway. Moreover, examination of LGN axons at one week post-lesion, a time when they would normally be waiting and branching within the visual subplate, indicated that the axons had already grown past their correct destination. These observations suggest that visual subplate neurons are involved in the process by which LGN axons select and subsequently grow into visual cortex. In contrast, subplate neurons do not appear to play a major role in the initial morphological development of the LGN itself. Subplate ablations did not alter dendritic growth or shapes of LGN projection neurons during the period under study, nor did it prevent the segregation of retinal ganglion cell axons into eye-specific layers. However, the overall size of the LGN was reduced, suggesting that there may be increased cell death of LGN neurons in the absence of subplate neurons. To examine whether subplate neurons beneath other neocortical areas play a similar role in the formation of thalamocortical connections, subplate neurons were deleted beneath auditory cortex at the onset of the waiting period for auditory thalamic axons. Subsequent DiI labeling revealed that in these animals the majority of MGN axons had grown past auditory cortex instead of innervating it. Taken together these observations underscore a general requirement for subplate neurons throughout neocortex in the process of cortical target selection and ingrowth by thalamic axons.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1993KY54800018

    View details for PubMedID 8325233

  • DEVELOPMENTAL MECHANISMS THAT GENERATE PRECISE PATTERNS OF NEURONAL CONNECTIVITY CELL Goodman, C. S., Shatz, C. J. 1993; 72: 77-98

    View details for Web of Science ID A1993KL70700006

    View details for PubMedID 8428376

  • NEURONAL DEATH, A TRADITION OF DYING JOURNAL OF NEUROBIOLOGY OPPENHEIM, R. W., Schwartz, L. M., Shatz, C. J. 1992; 23 (9): 1111-1115

    View details for Web of Science ID A1992JZ54900001

    View details for PubMedID 1469377

  • DIVIDING UP THE NEOCORTEX SCIENCE Shatz, C. J. 1992; 258 (5080): 237-238

    View details for Web of Science ID A1992JR86000016

    View details for PubMedID 1357747

  • The developing brain. Scientific American Shatz, C. J. 1992; 267 (3): 60-67

    View details for PubMedID 1502524

  • SYNAPSES FORMED BY IDENTIFIED RETINOGENICULATE AXONS DURING THE SEGREGATION OF EYE INPUT JOURNAL OF NEUROSCIENCE Campbell, G., Shatz, C. J. 1992; 12 (5): 1847-1858

    Abstract

    The synaptic organization of identified retinogeniculate axons was studied during the prenatal development of eye-specific layers in the LGN of the cat. During this period, retinogeniculate axons undergo stereotyped morphological changes. Retinogeniculate axons originating from one eye and passing through LGN territory destined to be solely innervated by the other eye (inappropriate territory) initially give rise to many side branches. As the eye-specific layers emerge, these axons elaborate extensive terminal arbors within territory appropriate to their eye of origin and concurrently retract their side branches from inappropriate territory (Sretavan and Shatz, 1986). These transient side branches may therefore represent a morphological substrate for the observed functional convergence of inputs from the two eyes onto common LGN neurons during prenatal development (Shatz and Kirkwood, 1984). This possibility was investigated by examining whether identified axons and their side branches form synapses in inappropriate territory. Three retinogeniculate axons from two fetuses aged embryonic day 53 (E53) and E57 were filled with HRP in an in vitro preparation, prior to being processed for electron microscopy (EM). The HRP-filled axons, originating from the contralateral eye, were first reconstructed at the light microscope level. The portion of axon passing through the center of ipsilaterally innervated layer A1 was then serially sectioned and reconstructed by EM. Two sets of 450 serial EM sections revealed that all three contralateral axons established synaptic contacts in ipsilateral territory. Many of these synapses were made by side branches and a few were even formed by the main axon trunks. Both side branches and trunks formed mainly en passant asymmetrical contacts that were associated with spherical synaptic vesicles and that were apposed to immature dendritic elements and dendritic shafts. For comparison, a portion of the same E53 axon within the future contralateral layer A was also serially sectioned and reconstructed for EM. Within this contralateral zone, the E53 axon formed synaptic contacts similar to those established in the ipsilateral region, except that in the appropriate zone they contained significantly more synaptic vesicles. These results demonstrate that axons from the contralateral eye can establish synapses in territory simultaneously innervated by the ipsilateral eye, both via side branches and by means of contacts along the main axon trunk. Thus, the development of eye-specific layers is accompanied by the formation and subsequent elimination of synapses that almost certainly represent a morphological substrate for the known transient functional convergence of inputs from the two eyes.

    View details for Web of Science ID A1992HT83700027

    View details for PubMedID 1578274

  • INVOLVEMENT OF SUBPLATE NEURONS IN THE FORMATION OF OCULAR DOMINANCE COLUMNS SCIENCE Ghosh, A., Shatz, C. J. 1992; 255 (5050): 1441-1443

    Abstract

    During development of the mammalian visual system, axon terminals of lateral geniculate nucleus (LGN) neurons, initially intermixed within layer 4 of the visual cortex, gradually segregate according to eye preference to form ocular dominance columns. In addition to LGN axons and layer 4 neurons, subplate neurons may also participate in interactions leading to column formation. Deletion of subplate neurons before the formation of ocular dominance columns prevents the segregation of LGN axons within layer 4. Thus, interactions between LGN axons and layer 4 neurons are not sufficient; subplate neurons are also required for formation of ocular dominance columns in the visual cortex.

    View details for Web of Science ID A1992HH74400059

    View details for PubMedID 1542795

  • How are specific connections formed between thalamus and cortex? Current opinion in neurobiology Shatz, C. J. 1992; 2 (1): 78-82

    Abstract

    During development precise thalamocortical connections are established, with reciprocal connections forming correctly in a laminar pattern as well as between the correct thalamic and cortical areas. Recent evidence suggests that both spatial and temporal cues may account for this specificity.

    View details for PubMedID 1638139

  • Synaptic Contacts and the Transient Dendritic Spines of Developing Retinal Ganglion Cells. The European journal of neuroscience Wong, R. O., Yamawaki, R. M., Shatz, C. J. 1992; 4 (12): 1387-1397

    Abstract

    The dendrites of ganglion cells in the mammalian retina become extensively remodelled during synapse formation in the inner plexiform layer. In particular, after birth in the cat, many short spiny protrusions are lost from the dendrites of ganglion cells during the time when ribbon, presumably bipolar, synapses appear in the inner plexiform layer and when conventional, presumed amacrine, synapses increase significantly in number. It has therefore been postulated that these transient spines may be the initial or preferred substrates for competitive interactions between amacrine or bipolar cell terminals that subsequently result in the formation of appropriate synapses onto the ganglion cells. If so, the majority of synapses made onto developing ganglion cells should be found on these dendritic spines. To test this hypothesis, we determined the synaptic connectivity of identified ganglion cells in the postnatal cat retina during the period of peak spine loss and synapse formation. The dendritic trees of ganglion cells were intracellularly filled with Lucifer yellow that was subsequently photo-oxidized into an electron-dense product suitable for electron microscopy. In serial reconstructions of the dendrites of a postnatal day 11 (P11) alpha ganglion cell and a P14 beta ganglion cell, conventional and ribbon synapses were found predominantly on dendritic shafts. Only three out of a total of 341 dendritic spines from the two cells received direct presynaptic input, all of which were conventional synapses. Thus, our observations suggest that the transient dendritic spines are not the preferred postsynaptic sites as previously suspected. However, it is possible that these structures play a different role in synaptogenesis, such as mediating interactions between retinal neurons that may lead to cell - cell recognition, a necessary step prior to synapse formation at the appropriate target sites (Cooper and Smith, Soc. Neurosci. Abstr., 14, 893, 1988).

    View details for PubMedID 12106402

  • PATHFINDING AND TARGET SELECTION BY DEVELOPING GENICULOCORTICAL AXONS JOURNAL OF NEUROSCIENCE Ghosh, A., Shatz, C. J. 1992; 12 (1): 39-55

    Abstract

    During development of the mammalian cerebral cortex, thalamic axons must grow into the telencephalon and select appropriate cortical targets. In order to begin to understand the cellular interactions that are important in cortical target selection by thalamic axons, we have examined the morphology of axons from the lateral geniculate nucleus (LGN) as they navigate their way to the primary visual cortex. The morphology of geniculocortical axons was revealed by placing the lipophilic tracer Dil into the LGN of paraformaldehyde-fixed brains from fetal and neonatal cats between embryonic day 26 (E26; gestation is 65 d) and postnatal day 7 (P7). This morphological approach has led to three major observations. (1) As LGN axons grow within the intermediate zone of the telencephalon toward future visual cortex (E30-40), many give off distinct interstitial axon collaterals that penetrate the subplate of nonvisual cortical areas. These collaterals are transient and are not seen postnatally. (2) There is a prolonged period during which LGN axons are restricted to the visual subplate prior to their ingrowth into the cortical plate; the first LGN axons arrive within visual subplate by E36 but are not detected in layer 6 of visual cortex until about E50. (3) Within the visual subplate, LGN axons extend widespread terminal branches. This represents a marked change in their morphology from the simple growth cones present earlier as LGN axons navigate en route to visual cortex. The presence of interstitial collaterals suggests that there may be ongoing interactions between LGN axons and subplate neurons along the entire intracortical route traversed by the axons. From the extensive branching of LGN axons within the visual subplate during the waiting period, it appears that they are not simply "waiting." Rather, LGN axons may participate in dynamic cellular interactions within the subplate long before they contact their ultimate target neurons in layer 4. These observations confirm the existence of a prolonged waiting period in the development of thalamocortical connections and provide important morphological evidence in support of the previous suggestion that interactions between thalamic axons and subplate neurons are necessary for cortical target selection.

    View details for Web of Science ID A1992HA64400004

    View details for PubMedID 1729444

  • CHANGING PATTERNS OF SYNAPTIC INPUT TO SUBPLATE AND CORTICAL PLATE DURING DEVELOPMENT OF VISUAL-CORTEX JOURNAL OF NEUROPHYSIOLOGY FRIAUF, E., Shatz, C. J. 1991; 66 (6): 2059-2071

    Abstract

    1. The development of excitatory activation in the visual cortex was studied in fetal and neonatal cats. During fetal and neonatal life, the immature cerebral cortex (the cortical plate) is sandwiched between two synaptic zones: the marginal zone above, and an area just below the cortical plate, the subplate. The subplate is transient and disappears by approximately 2 mo postnatal. Here we have investigated whether the subplate and the cortical plate receive functional synaptic inputs in the fetus, and when the adultlike pattern of excitatory synaptic input to the cortical plate appears during development. 2. Extracellular field potential recording to electrical stimulation of the optic radiation was performed in slices of cerebral cortex maintained in vitro. Laminar profiles of field potentials were converted by the current-source density (CSD) method to identify the spatial and temporal distribution of neuronal excitation within the subplate and the cortical plate. 3. Between embryonic day 47 (E47) and postnatal day 28 (P28; birth, E65), age-related changes occur in the pattern of synaptic activation of neurons in the cortical plate and the subplate. Early in development, at E47, E57, and P0, short-latency (probably monosynaptic) excitation is most obvious in the subplate, and longer latency (presumably polysynaptic) excitation can be seen in the cortical plate. Synaptic excitation in the subplate is no longer apparent at P21 and P28, a time when cell migration is finally complete and the cortical layers have formed. By contrast, excitation in the cortical plate is prominent in postnatal animals, and the temporal and spatial pattern has changed. 4. The adultlike sequence of synaptic activation in the different cortical layers can be seen by P28. It differs from earlier ages in several respects. First, short-latency (probably monosynaptic) excitation can be detected in cortical layer 4. Second, multisynaptic, long-lasting activation is present in layers 2/3 and 5. 5. Our results show that the subplate zone, known from anatomic studies to be a synaptic neurophil during development, receives functional excitatory inputs from axons that course in the developing white matter. Because the only mature neurons present in this zone are the subplate neurons, we conclude that subplate neurons are the principal, if not the exclusive, recipients of this input. The results suggest further that the excitation in the subplate in turn is relayed to neurons of the cortical plate via axon collaterals of subplate neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1991GW56400024

    View details for PubMedID 1812236

  • REMODELING OF RETINAL GANGLION-CELL DENDRITES IN THE ABSENCE OF ACTION-POTENTIAL ACTIVITY JOURNAL OF NEUROBIOLOGY Wong, R. O., Herrmann, K., Shatz, C. J. 1991; 22 (7): 685-697

    Abstract

    The dendrites of ganglion cells in the retina have an excess number of spines and branches that are normally lost during the first postnatal month of development. We investigated whether this dendritic remodeling can be prevented when the action potential activity of ganglion cells is abolished by chronic intraocular injections of tetrodotoxin (TTX) during the first 4 or 5 postnatal weeks in the cat. Dendritic tree morphologies of alpha and beta ganglion cells from TTX-treated, non-TTX-treated (contralateral eye), and normal control retinae were compared after intracellular filling with Lucifer yellow. Qualitative observations and quantitative measurements indicate that TTX treatment does not prevent the normally occurring loss of spines and dendritic branches. Indeed, the dendritic trees of both alpha and beta cells in TTX injected eyes actually have even fewer spines and branches than normal cells at equivalent ages. However, because the total dendritic lengths of these cells are also reduced after TTX blockade, spine density is indistinguishable from untreated animals at the same age. In addition, although dendritic field areas are not altered with treatment, the complexity of the dendritic trees is reduced. These observations suggest that dendritic remodeling can occur in the absence of ganglion cell action potential activity. Thus, the factors that influence the dendritic and axonal development of retinal ganglion cells must differ, because similar TTX treatment during the period of axonal remodeling does have profound effects on the final pattern of terminal arborizations.

    View details for Web of Science ID A1991GH71100003

    View details for PubMedID 1662709

  • MORPHOLOGY OF PIONEER AND FOLLOWER GROWTH CONES IN THE DEVELOPING CEREBRAL-CORTEX JOURNAL OF NEUROBIOLOGY Kim, G. J., Shatz, C. J., McConnell, S. K. 1991; 22 (6): 629-642

    Abstract

    In the developing nervous systems of both invertebrates and vertebrates, neurons must develop precise sets of axonal connections. One strategy used by both orders of animals is to generate a special class of neurons whose axons "pioneer" the first pathways between these cells and their targets. In the developing mammalian telencephalon, the subplate neurons (which are among the first neurons to be generated in development) extend axons to long-distance subcortical targets before the neurons of the deep cortical layers 5 and 6 have been generated. The axons of layer 5 and 6 neurons later follow a similar pathway to form permanent subcortical projections to the thalamus and tectum, and thereafter the vast majority of subplate neurons die. These results have generated the hypothesis that subplate axons may actually be required for the axons of layer 5 and 6 neurons to innervate their appropriate subcortical targets. The complexity of growth cones has previously been correlated with axonal decision making: differences in growth cone morphologies have been noted in comparisons of leading versus following axons (LoPresti, Macagno, and Levinthal, 1973; Nordlander, 1987; Yaginuma, Homma, Kunzi, and Oppenheim, 1991), and at choice points along axon pathways (Raper, Bastiani, and Goodman, 1983; Tosney and Landmesser, 1985; Caudy and Bentley, 1986a,b; Bovolenta and Mason, 1987; Holt, 1989; Bovolenta and Dodd, 1990; Yaginuma et al., 1991). Thus, as a first step toward addressing the question of whether the axons of deep-layer neurons simply follow subplate axons to their targets, we have studied the morphology of cortical growth cones at various points along the corticothalamic pathway and at different stages of development. We examined the brains of fetal ferrets and cats at ages ranging from embryonic days (E) 24 to E50, using the fluorescent lipophilic tracer 1,1-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate (DiI) to reveal the axons and growth cones of cortical neurons. Growth cones were drawn, and quantitative measurements of their complexity were made by counting filopodia and calculating their surface area. No morphological differences were found among growth cones at different points along the corticothalamic pathway at a given age. However, growth cones belonging to early-generated cells (likely to be subplate neurons) are significantly larger and more complex than are the growth cones of later-generated cortical neurons. This evidence is consistent with the suggestion that subplate growth cones actively pioneer the corticothalamic pathway, and that the axons of layer 5 and 6 neurons follow it.

    View details for Web of Science ID A1991GB72100007

    View details for PubMedID 1919567

  • SYNCHRONOUS BURSTS OF ACTION-POTENTIALS IN GANGLION-CELLS OF THE DEVELOPING MAMMALIAN RETINA SCIENCE Meister, M., Wong, R. O., Baylor, D. A., Shatz, C. J. 1991; 252 (5008): 939-943

    Abstract

    The development of orderly connections in the mammalian visual system depends on action potentials in the optic nerve fibers, even before the retina receives visual input. In particular, it has been suggested that correlated firing of retinal ganglion cells in the same eye directs the segregation of their synaptic terminals into eye-specific layers within the lateral geniculate nucleus. Such correlations in electrical activity were found by simultaneous recording of the extracellular action potentials of up to 100 ganglion cells in the isolated retina of the newborn ferret and the fetal cat. These neurons fired spikes in nearly synchronous bursts lasting a few seconds and separated by 1 to 2 minutes of silence. Individual bursts consisted of a wave of excitation, several hundred micrometers wide, sweeping across the retina at about 100 micrometers per second. These concerted firing patterns have the appropriate spatial and temporal properties to guide the refinement of connections between the retina and the lateral geniculate nucleus.

    View details for Web of Science ID A1991FM04000028

    View details for PubMedID 2035024

  • IMPULSE ACTIVITY AND THE PATTERNING OF CONNECTIONS DURING CNS DEVELOPMENT NEURON Shatz, C. J. 1990; 5 (6): 745-756

    View details for Web of Science ID A1990EQ38100001

    View details for PubMedID 2148486

  • REQUIREMENT FOR SUBPLATE NEURONS IN THE FORMATION OF THALAMOCORTICAL CONNECTIONS NATURE Ghosh, A., Antonini, A., McConnell, S. K., Shatz, C. J. 1990; 347 (6289): 179-181

    Abstract

    The neurons of layer 4 in the adult cerebral cortex receive their major ascending inputs from the thalamus. In development, however, thalamic axons arrive at the appropriate cortical area long before their target layer 4 neurons have migrated into the cortical plate. The axons accumulate and wait in the zone below the cortical plate, the subplate, for several weeks before invading the cortical plate. The subplate is a transient zone that contains the first postmitotic neurons of the telencephalon. These neurons mature well before other cortical neurons, and disappear by cell death after the thalamic axons have grown into the overlying cortical plate. The close proximity of growing thalamocortical axons and subplate neurons suggests that they might be involved in interactions important for normal thalamocortical development. Here we show that early in development the deletion of subplate neurons located beneath visual cortex prevents axons from the lateral geniculate nucleus of the thalamus from recognizing and innervating visual cortex, their normal target. In the absence of subplate neurons, lateral geniculate nucleus axons continue to grow in the white matter past visual cortex despite the presence of their target layer 4 neurons. Thus the transient subplate neurons are necessary for appropriate cortical target selection by thalamocortical axons.

    View details for Web of Science ID A1990DY35200061

    View details for PubMedID 2395469

  • RELATION BETWEEN PUTATIVE TRANSMITTER PHENOTYPES AND CONNECTIVITY OF SUBPLATE NEURONS DURING CEREBRAL CORTICAL DEVELOPMENT EUROPEAN JOURNAL OF NEUROSCIENCE Antonini, A., Shatz, C. J. 1990; 2 (9): 744-761
  • FUNCTIONAL SYNAPTIC CIRCUITS IN THE SUBPLATE DURING FETAL AND EARLY POSTNATAL-DEVELOPMENT OF CAT VISUAL-CORTEX JOURNAL OF NEUROSCIENCE FRIAUF, E., McConnell, S. K., Shatz, C. J. 1990; 10 (8): 2601-2613

    Abstract

    Among the first postmitotic cells of the cerebral cortex is a special population located below the cortical plate: the subplate neurons. These neurons reach a high degree of morphological maturity during fetal life, well before the neurons of the cortical layers have matured, yet nearly all of these cells die after birth in the cat. Subplate neurons are also known to receive synaptic contacts. Here we have investigated whether these contacts are functional by making intracellular recordings from subplate neurons in cortical slices maintained in vitro. Subplate neurons were identified based on their location and morphology by injecting them with biocytin following the intracellular recordings. At all ages studied between embryonic day 50 and postnatal day 9, electrical stimulation of the optic radiations elicited EPSPs and synaptic and antidromic spikes in subplate neurons, indicating that some of the synapses seen at the ultrastructural level are indeed capable of synaptic transmission. The spiking patterns of 39 morphologically identified subplate neurons were examined by injecting depolarizing current, which revealed that a large majority gave only a single spike or a brief train of spikes in response to maintained depolarization, in contrast to the regular spiking pattern found in many neurons of adult cortex. Biocytin injections into subplate neurons revealed that they are a morphologically heterogeneous population with respect to their dendritic branching patterns; roughly half were inverted pyramids, the classic subplate neuron morphology. The axonal processes of subplate neurons were remarkable in that many not only arborized within the subplate, but also entered the cortical plate and terminated in the marginal zone. At early postnatal ages, these axons also gave off collaterals within cortical layer 4. The results of this study indicate that subplate neurons participate in synaptic microcircuits during development. While the presynaptic identity of the input to subplate neurons is not known conclusively, it is likely that geniculocortical axons, which wait in close proximity to subplate neurons, contribute significantly. The pattern of axonal branching of subplate neurons also implies that information conferred to subplate neurons may be relayed, in turn, to the neurons of cortical layer 4. Finally with the death of subplate neurons, the geniculocortical axons leave the subplate and invade the cortical plate to innervate directly the neurons of layer 4. Thus, subplate neurons may function as a crucial, but transient synaptic link between waiting geniculocortical axons and their ultimate target cells in the cortex.

    View details for Web of Science ID A1990DW22100009

    View details for PubMedID 2388080

  • COMPETITIVE INTERACTIONS BETWEEN RETINAL GANGLION-CELLS DURING PRENATAL DEVELOPMENT JOURNAL OF NEUROBIOLOGY Shatz, C. J. 1990; 21 (1): 197-?

    Abstract

    In the mammalian visual system, retinal ganglion cell axons terminate within the LGN in a series of alternating eye-specific layers. These layers are not present initially during development. In the cat they emerge secondarily following a prenatal period in which originally intermixed inputs from the two eyes gradually segregate from each other to give rise to the characteristic set of layers by birth. Many lines of evidence suggest that activity-dependent competitive interactions between ganglion cell axons from the two eyes for LGN neurons play an important role in the final patterning of retinogeniculate connections. Studies of the branching patterns of individual ganglion cell axons suggest that during the period when inputs from the two eyes are intermixed, axons from one eye send side branches into territory later occupied exclusively by axons from the other eye. Ultrastructural studies indicate that these branches in fact are sites of synaptic contacts, which are later eliminated since the side branches disappear as axons form their mature terminal arbors in appropriate territory. In vitro microelectrode recordings from LGN neurons indicate that they can receive convergent synaptic excitation from electrical stimulation of the optic nerves before but not after the eye-specific layers form, suggesting that at least some of the synaptic contacts seen at the ultrastructural level are functional. Finally, experiments in which tetrodotoxin was infused intracranially during the two week period during which the eye-specific layers normally form demonstrate that it is possible to prevent, or at least delay, the formation of the layers. Accordingly, individual axons fail to develop their restricted terminal arbor branching pattern and instead branch widely throughout the LGN. These results indicate that all of the machinery necessary for synaptic function and competition is present during fetal life. Moreover, it is highly likely that neuronal activity is required for the formation of the eye-specific layers. If so, then activity would have to be present in the form of spontaneously generated action potentials, since vision is not possible at these early ages. Thus, the functioning of the retinogeniculate system many weeks before it is put to the use for which it is ultimately designed may contribute to the final patterning of connections present in the adult.

    View details for Web of Science ID A1990CQ75500012

    View details for PubMedID 2181063

  • NERVE GROWTH-FACTOR RECEPTOR IMMUNOREACTIVITY IS TRANSIENTLY ASSOCIATED WITH THE SUBPLATE NEURONS OF THE MAMMALIAN CEREBRAL-CORTEX PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Allendoerfer, K. L., Shelton, D. L., Shooter, E. M., Shatz, C. J. 1990; 87 (1): 187-190

    Abstract

    Nerve growth factor and its receptor (NGFR) are known to be present in diverse embryonic and neonatal central nervous system tissues, including the cerebral cortex. However, the identity of the cortical cells expressing NGFR immunoreactivity has not been established. We have used immunolabeling coupled with [3H]thymidine autoradiography to identify such cells in ferret and cat brain. Polyclonal antibodies raised against a synthetic peptide corresponding to a conserved amino acid sequence of the NGFR were used for this purpose. Western (immunologic) blot analyses show that these antibodies specifically recognize NGFR and precursor proteins. In both species, NGFR immunoreactivity is primarily associated with the early generated and transient subplate neuron population of the developing neocortex, as indicated by the following evidence: the immunoreactive cells (i) are located directly beneath the developing cortical plate, (ii) frequently have the inverted pyramid shape characteristic of subplate neurons, and (iii) can be labeled by an injection of [3H]thymidine on embryonic day (E) 28, a time when only subplate neurons are being generated. Intense NGFR immunostaining is seen on the cell bodies of these neurons as early as E30, several days after their last round of cell division, and this immunostaining remains strong for approximately 3 weeks. The NGFR immunoreactivity begins to decline around E52 and has disappeared from the region altogether by E60, at which time subplate neurons begin to die. The cellular localization and timing of expression suggest that the NGFR may play a role in the maintenance of subplate neurons and in the maturation of the cerebral cortex.

    View details for Web of Science ID A1990CH19000040

    View details for PubMedID 2153287

  • The Effects of Prenatal Intracranial Infusion of Tetrodotoxin on Naturally Occurring Retinal Ganglion Cell Death and Optic Nerve Ultrastructure. The European journal of neuroscience Friedman, S., Shatz, C. J. 1990; 2 (3): 243-253

    Abstract

    In the developing vertebrate nervous system, cell death is known to play an important role in determining final neuron number. Retinal ganglion cells in the cat's visual system undergo a massive elimination by cell death during the prenatal period between E44 (age of embryo in days) and birth (= E65). We have examined whether neural activity contributes to ganglion cell death by infusing tetrodotoxin (TTX), a blocker of the voltage-sensitive sodium channel. TTX was infused intracranially via osmotic minipumps implanted in utero at E42. The effects of the TTX treatment on ganglion cell death and optic nerve ultrastructure were examined at either E49 or E57 by electron microscopy and quantitative analysis of optic axon number. The numbers of optic nerve axons counted in the optic nerves of animals after either 1 or 2 weeks of TTX treatment were not significantly different from the counts in normal animals at comparable ages: E49 TTX-3.2 x 105; E48 normal-3.3 x 105; E57 TTX-2.1 x 105; E59 normal-2.4 x 105. These results suggest that retinal ganglion cells cannot be rescued from death by blockade of neural activity central to the optic chiasma. However, the ultrastructure of optic nerves following 2 weeks of TTX infusion was quite abnormal. The usual packaging of axons into fascicles by glia was disrupted by the presence of many pale, organelle-poor processes that were about 10 times larger in their cross-sectional areas than axons in either normal or TTX-treated nerves. Examination of these processes in serial transverse or in longitudinal electron microscope (EM) sections of the nerve revealed that they were most likely glial in origin. The ultrastructural organization of the optic nerve following 1 week of TTX treatment was normal, indicating that this effect on glial ultrastructure is either cumulative or delayed in onset. These results suggest that while the conduction of action potentials to the terminals of retinogeniculate axons may not play a significant role in regulating ganglion cell number prenatally, it may affect the normal maturation of optic nerve glia.

    View details for PubMedID 12106051

  • Relation Between Putative Transmitter Phenotypes and Connectivity of Subplate Neurons During Cerebral Cortical Development. The European journal of neuroscience Antonini, A., Shatz, C. J. 1990; 2 (9): 744-761

    Abstract

    During development, the earliest generated neurons of the mammalian telencephalon reside in a region of the white matter, the subplate, just beneath the cortical plate. Neurons in the subplate are only transiently present in the telencephalon: shortly after birth in the cat the majority have disappeared. During their brief life, however, subplate neurons mature; they extend long-distance and local projections, and express immunoreactivity for GABA and several neuropeptides. In the present study we examined the relation between possible transmitter phenotypes of subplate neurons and their connectivity. To do so, we used a double-label technique in which immunohistochemistry for neuropeptide Y (NPY), somatostatin (SRIF) or calbindin (CaBP) was combined with retrograde tracing. Experiments were performed in neonatal cats and in ferret kits at equivalent postconceptional ages, times when subplate neurons are numerous. Subplate neurons immunoreactive for neuropeptides and CaBP could be double-labelled by an injection of retrograde tracer either into the cortical plate or the white matter, indicating that this particular subset of subplate neurons can make local circuit projections. In contrast, peptide or CaBP immunoreactive subplate neurons could never be retrogradely labelled from a tracer injection into the thalamus. Taken together, these observations indicate that subplate neurons immunoreactive for NPY, SRIF and CaBP are likely to be interneurons exclusively. On the other hand, subplate neurons with long-distance projections to the thalamus or the contralateral hemisphere could be labelled by the retrograde transport of d-[3H]aspartate, suggesting that at least some projection subplate neurons might use an excitatory amino acid as a neurotransmitter. These results indicate that there is a defined relationship between the putative transmitter phenotypes of subplate neurons and their patterns of projection. Interneurons of the subplate express peptidergic properties while projection neurons to the thalamus may use an excitatory amino acid. Thus, these basic organizational features of the transient subplate are reminiscent of those found in the adult cortical layers.

    View details for PubMedID 12106275

  • PIONEER NEURONS AND TARGET SELECTION IN CEREBRAL CORTICAL DEVELOPMENT BRAIN / Shatz, C. J., Ghosh, A., McConnell, S. K., Allendoerfer, K. L., FRIAUF, E., Antonini, A. 1990; 55: 469-480
  • SUBPLATE NEURONS PIONEER THE 1ST AXON PATHWAY FROM THE CEREBRAL-CORTEX SCIENCE McConnell, S. K., Ghosh, A., Shatz, C. J. 1989; 245 (4921): 978-982

    Abstract

    During the development of the nervous system, growing axons must traverse considerable distances to find their targets. In insects, this problem is solved in part by pioneer neurons, which lay down the first axonal pathways when distances are at a minimum. Here the existence of a similar kind of neuron in the developing mammalian telencephalon is described. These are the subplate cells, the first postmitotic neurons of the cerebral cortex. Axons from subplate neurons traverse the internal capsule and invade the thalamus early in fetal life, even before the neurons of cortical layers 5 and 6, which will form the adult subcortical projections, are generated. During postnatal life, after the adult pattern of axonal projections is firmly established, most subplate neurons disappear. These observations raise the possibility that the early axonal scaffold formed by subplate cells may prove essential for the establishment of permanent subcortical projections.

    View details for Web of Science ID A1989AM93300029

    View details for PubMedID 2475909

  • THE EARLIEST-GENERATED NEURONS OF THE CAT CEREBRAL-CORTEX - CHARACTERIZATION BY MAP2 AND NEUROTRANSMITTER IMMUNOHISTOCHEMISTRY DURING FETAL LIFE JOURNAL OF NEUROSCIENCE CHUN, J. J., Shatz, C. J. 1989; 9 (5): 1648-1667

    Abstract

    The earliest-generated neurons of the cat cerebral cortex have been studied here during development using a combination of 3H-thymidine birthdating with immunohistochemistry for the neuron-specific protein MAP2 or for several neuropeptides/transmitters. These neurons are the first postmitotic cells of the cortex, with birthdates during the 1-week period preceding the genesis of cells of the adult cerebral cortex (Luskin and Shatz, 1985a; Chun et al., 1987). However, they are transient and the majority disappear by adulthood (Luskin and Shatz, 1985a; Chun and Shatz, 1989). When autoradiographic birthdating is combined with MAP2 immunostaining during fetal life, the entire population of these early-generated neurons appears to be stained, resulting in labeled bands above and below the cortical plate. The band above the cortical plate (in the marginal zone) contains early-generated neurons with horizontal morphologies, while the thicker band beneath the cortical plate (within the intermediate zone) contains the somata of early-generated neurons and their elaborate processes that are frequently directed towards the ventricular surface. In view of the correspondence between the location of the early-generated neurons and the MAP2-immunostained band beneath the cortical plate, we suggest that this combined approach can be used to define accurately the subdivision of the intermediate zone known as the subplate. The early-generated neurons are also immunoreactive for GABA, neuropeptide Y (NPY), somatostatin (SRIF), and cholecystokinin (CCK) during fetal life. While GABA, NPY, and SRIF immunostaining could be detected by embryonic day 50 (E50), that for CCK was not found until E60. Moreover, there is a relationship between neuropeptide immunoreactivity and location within the cerebral wall. The marginal-zone neurons are immunoreactive only for CCK. The subplate neurons are immunoreactive for CCK, SRIF, and NPY. Most of those immunoreactive for SRIF tend to be clustered within the upper part of the subplate, while those immunoreactive for NPY tend to be located more deeply. Cells immunoreactive for GABA are more uniformly distributed throughout the cerebral wall. These observations demonstrate directly that the marginal zone and subplate contain peptide- and GABA-immunoreactive neurons that belong to the earliest-generated cell population of the cerebral cortex. The presence of these early-generated neurons, which achieve a remarkable degree of maturity during fetal life, suggests that they perform an essential, yet transient, role in the development of the cerebral cortex.

    View details for Web of Science ID A1989U761100018

    View details for PubMedID 2566660

  • INTERSTITIAL-CELLS OF THE ADULT NEOCORTICAL WHITE MATTER ARE THE REMNANT OF THE EARLY GENERATED SUBPLATE NEURON POPULATION JOURNAL OF COMPARATIVE NEUROLOGY CHUN, J. J., Shatz, C. J. 1989; 282 (4): 555-569

    Abstract

    The postnatal fate of the first-generated neurons of the cat cerebral cortex was examined. These neurons can be identified uniquely by 3H-thymidine exposure during the week preceding the neurogenesis of cortical layer 6. Previous studies in which 3H-thymidine birthdating at embryonic day 27 (E27) was combined with immunohistochemistry have shown that these neurons are present in large numbers during fetal and early postnatal life within the subplate (future white matter), that they are immunoreactive for the neuron-specific protein MAP2 and for the putative neurotransmitters GABA, NPY, SRIF, and CCK. Here, the same techniques were used to follow the postnatal location and disappearance of the early generated subplate neuron population. At birth (P0), subplate neurons showing immunoreactivity for GABA, NPY, SRIF, or CCK are present in large numbers and at high density within the white matter throughout the neocortex, and the entire population can be observed as a dense MAP2-immunoreactive band situated beneath cortical layer 6. Between P0 and P401 (adulthood), the MAP2-immunostained band disappears so that comparatively few MAP2-immunoreactive neurons remain within the white matter. There is a corresponding decrease in the number and density of neurons stained with antibodies against neurotransmitters. In each instance, these neurons could be double-labeled by the administration of 3H-thymidine at E27, indicating that they are the remnants of the early generated subplate neuron population. The major period of decrease occurs during the first 4 postnatal weeks, and adult values are attained by 5 months. Within the white matter of the lateral gyrus (visual cortex), the density of immunostained neurons decreases dramatically: MAP2, 82%, SRIF, 81%, and NPY, 96%. While SRIF-immunoreactive neurons compose a nearly constant percentage of MAP2-immunoreactive neurons in the white matter between P0 (22%) and P401 (23%), those immunoreactive for NPY decline from 18 to 4%. These changes occur during the same period in which there is less than a twofold increase in white matter area. These observations indicate that the interstitial neurons of the adult neocortical white matter are the oldest neurons of the cerebral cortex since most if not all are derived from the subplate neuron population. In addition, a quantitative analysis suggests that the postnatal decline in subplate neuron density cannot be accounted for solely through dilution by differential growth of the white matter and most likely reflects an absolute decrease in subplate neuron number.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1989U535700006

    View details for PubMedID 2566630

  • RETINAL GANGLION BETA-CELLS PROJECT TRANSIENTLY TO THE SUPERIOR COLLICULUS DURING DEVELOPMENT PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ramoa, A. S., Campbell, G., Shatz, C. J. 1989; 86 (6): 2061-2065

    Abstract

    In adult cats, retinal ganglion cells of the beta class project almost exclusively to the lateral geniculate nucleus rather than to the superior colliculus (SC). We have examined whether this target specificity is present during early development. To identify ganglion cells that send axons to the SC in development, rhodamine-labeled microspheres were deposited in the SC at embryonic day (E) 38, E43, or postnatal day (P) 4. Retinae were then removed between E56 and P32 and kept alive in a tissue-slice chamber so that ganglion cells that had been retrogradely labeled with microspheres could be injected intracellularly with Lucifer yellow to reveal their morphological class. Many beta cells could be retrogradely labeled by microspheres injected into the SC at E38 or E43. They were indistinguishable from beta cells projecting to the lateral geniculate nucleus and were found even when a single injection was restricted to the caudal portion of the SC. In contrast, beta cells could not be retrogradely labeled by microspheres injected into the SC at P4. The disappearance of a beta-cell projection to the SC cannot be explained entirely by cell death since as late as P32, well after the major period of ganglion cell death, many beta ganglion cells labeled with microspheres at E38 were still present. These observations suggest that many beta cells initially extend an axon collateral to the SC that is subsequently lost some time after E43. Thus, to achieve the remarkable specificity present in the adult visual system, beta cells must withdraw axon collaterals from an entire target nucleus. Similar collateral elimination may give rise to the specificity of afferent connections in other sensory systems.

    View details for Web of Science ID A1989T788900068

    View details for PubMedID 2467298

  • MODIFICATION OF RETINAL GANGLION-CELL AXON MORPHOLOGY BY PRENATAL INFUSION OF TETRODOTOXIN NATURE Sretavan, D. W., Shatz, C. J., Stryker, M. P. 1988; 336 (6198): 468-471

    Abstract

    The cellular mechanisms by which the axons of individual neurons achieve their precise terminal branching patterns are poorly understood. In the visual system of adult cats, retinal ganglion cell axons from each eye form narrow cylindrical terminal arborizations restricted to alternate non-overlapping layers within the lateral geniculate nucleus (LGN). During prenatal development, axon arborizations from the two eyes are initially simple in shape and are intermixed with each other; they then gradually segregate to form complex adult-like arborizations in separate eye-specific layers by birth. Here we report that ganglion cell axons exposed to tetrodotoxin (TTX) to block neuronal activity during fetal life fail to form the normal pattern of terminal arborization. Individual TTX-treated axon arborizations are not stunted in their growth, but instead produce abnormally widespread terminal arborizations which extend across the equivalent of approximately two eye-specific layers. These observations suggest that during fetal development of the central nervous system, the formation of morphologically appropriate and correctly located axon terminal arborizations within targets is brought about by an activity-dependent process.

    View details for Web of Science ID A1988R135800056

    View details for PubMedID 2461517

  • DENDRITIC GROWTH AND REMODELING OF CAT RETINAL GANGLION-CELLS DURING FETAL AND POSTNATAL-DEVELOPMENT JOURNAL OF NEUROSCIENCE Ramoa, A. S., Campbell, G., Shatz, C. J. 1988; 8 (11): 4239-4261

    Abstract

    We have studied the development of retinal ganglion cell morphology in the cat's visual system from early fetal to postnatal times. In particular, we have examined the contribution of growth and remodeling to the establishment of mature retinal ganglion cell form. Ganglion cells were identified by retrograde labeling with rhodamine latex microspheres deposited in the superior colliculus and lateral geniculate nucleus between embryonic day 34 (E34; birth = E65) and adulthood. To reveal the fine morphological details of retrogradely labeled ganglion cells, 48 hr later Lucifer yellow was injected intracellularly in living retinae that had been dissected and maintained in vitro. Our results show that at E35-37 the majority of ganglion cells are very simple in morphology, with a few dendritic processes that are generally aligned in a radial direction towards or away from the optic disc. During the ensuing 2 week period, there is a progressive growth and elaboration of dendrites. By E50, some ganglion cells resembling the adult alpha, beta, and gamma classes can be identified based on comparisons of the appearance and dimensions of their dendritic trees and somata with neighboring filled cells. However, ganglion cell dendrites and axons at this age express several transient morphological features. The axons of ganglion cells give rise to delicate processes originating from the intraretinal portion of the axon, including side branches, present in about half of the cells, and occasionally bifurcations that give rise to axon collaterals. These transient axonal features are present throughout development, including the neonatal period; no axon collaterals were observed after postnatal day 15, while axonal side branches persisted even at P31 but were gone by adulthood. Ganglion cell dendrites exhibit excessive branches and exuberant somatic and dendritic spines. Quantitative analysis of these processes shows that after E45 dendritic trees increase dramatically in complexity, reaching the peak number of spines and branch points by the first week of postnatal life. The number of dendritic processes then falls abruptly to reach near-adult levels by the end of the first postnatal month. Even though dendritic morphology closely resembles that seen in the adult at this age, ganglion cell bodies and dendrites must continue to grow to reach their adult size.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1988Q949200023

    View details for PubMedID 3183722

  • PRENATAL TETRODOTOXIN INFUSION BLOCKS SEGREGATION OF RETINOGENICULATE AFFERENTS SCIENCE Shatz, C. J., Stryker, M. P. 1988; 242 (4875): 87-89

    Abstract

    In the adult mammalian visual system, ganglion cell axons from the two eyes are segregated from each other into separate layers within their principal target, the lateral geniculate nucleus. The involvement of spontaneously generated action potential activity in the process of segregation was investigated during the fetal period in which segregation normally occurs in the cat, between embryonic day 45 (E45) and birth (E65). Tetrodotoxin, which blocks the voltage-sensitive sodium channel, was used to prevent action potentials. Fetuses received continuous intracranial infusions of tetrodotoxin from osmotic minipumps implanted in utero on E42. After a 2-week infusion, intraocular injections of anterograde tracers revealed that tetrodotoxin prevented segregation. The contralateral projection filled the lateral geniculate nucleus uniformly, and the ipsilateral projection expanded to occupy most of what would normally be contralaterally innervated layer A. Thus, in the fetus, long before the onset of vision, spontaneous action potential activity is likely to be present in the visual system and to contribute to the segregation of the retinogeniculate pathway.

    View details for Web of Science ID A1988Q391900040

    View details for PubMedID 3175636

  • AXON ARBORS OF X AND Y RETINAL GANGLION-CELLS ARE DIFFERENTIALLY AFFECTED BY PRENATAL DISRUPTION OF BINOCULAR INPUTS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Garraghty, P. E., Shatz, C. J., Sretavan, D. W., Sur, M. 1988; 85 (19): 7361-7365

    Abstract

    In the mammalian visual system, the terminal arbors of retinal ganglion cell axons from the two eyes are restricted to mutually exclusive territories within their thalamic target, the lateral geniculate nucleus (LGN). Here we have investigated some of the factors that determine the adult morphology of terminal arbors in the cat's retinogeniculate system. Removal of one eye during prenatal life at a time when retinogeniculate axons from the two eyes are extensively intermixed within the LGN perturbs the subsequent morphological development of some but not all axons from the remaining eye. The presence of terminal arbors qualitatively normal in size, shape, and location within the LGN suggests that for some retinal axons, ongoing binocular interactions throughout prenatal life are not needed for the development of normal arbor morphology. However, many of the axons form arbors of abnormal size or location, suggesting that such features of axon morphology are not intrinsically determined for these axons but may be susceptible to external influences. Electrophysiological studies reveal that the abnormal arbors all belong to the functionally distinct Y class of retinal ganglion cells, whereas the normal arbors all belong to X cells. The different responses of X and Y axons to prenatal enucleation demonstrate that during development subsets of a single neuronal population projecting to the same target in the central nervous system can be under different developmental controls for axon arbor differentiation.

    View details for Web of Science ID A1988Q358500068

    View details for PubMedID 3174640

  • REDISTRIBUTION OF SYNAPTIC VESICLE ANTIGENS IS CORRELATED WITH THE DISAPPEARANCE OF A TRANSIENT SYNAPTIC ZONE IN THE DEVELOPING CEREBRAL-CORTEX NEURON CHUN, J. J., Shatz, C. J. 1988; 1 (4): 297-310

    Abstract

    To examine the distribution of synaptic vesicle antigens during development of the cerebral cortex, antibodies against synapsin I and p65 were used on sections of cat cerebral cortex between E40 and adulthood. In the adult, the layers of the cerebral cortex are immunoreactive for each of these antigens, while the white matter is free of staining. In contrast, the fetal and neonatal pattern of immunostaining is reversed: the cortical plate (future cortical layers) is devoid of immunoreactivity, while the marginal (future layer 1) and the intermediate zones (future white matter) are stained. Electron microscopic immunohistochemistry shows that immunolabeling is associated with presynaptic nerve terminals in the adult and during development. These observations suggest that during development the white matter is a transient synaptic neuropil and that a global redistribution of synapses takes place as the mature pattern of connections within the cerebral cortex emerges.

    View details for Web of Science ID A1988P012900005

    View details for PubMedID 3152420

  • ABNORMAL PIGMENTATION AND UNUSUAL MORPHOGENESIS OF THE OPTIC STALK MAY BE CORRELATED WITH RETINAL AXON MISGUIDANCE IN EMBRYONIC SIAMESE CATS JOURNAL OF COMPARATIVE NEUROLOGY Webster, M. J., Shatz, C. J., Kliot, M., Silver, J. 1988; 269 (4): 592-611

    Abstract

    Studies of albino rodents have shown that an absence of pigment in the developing optic stalk may alter the position of the first retinal fibers that grow toward the brain, thereby disrupting the gross topographic relationship of fibers in the nerve (Silver and Sapiro: J. Comp. Neurol. 202:521-538, '81). The abnormalities associated with albinism are more extensive in the Siamese cat than-in previously studied species. Therefore, any abnormalities in differentiation of the stalk and axon guidance may be more readily detected. To investigate the guidance and/or misguidance of optic axons, light and electron microscope analyses were made of serial sections through the optic stalk in normally pigmented and Siamese fetal cats. On E20, before axons enter the optic stalk, the only clear morphological distinction between Siamese and normal cats is the distribution of pigment in the stalk. Pigment is found in the dorsal stalk cells of the normal cat for 200 microns from the optic disc. Although the retinal pigment epithelium of the Siamese optic stalk. By E23 axons invade the ventral optic stalk in both strains. Concurrent with the early stages of axonal exit from the retina, there is complete separation of the stalk's dorsal and ventral tiers. As the cleavage occurs, basal lamina invaginates into the zone of separation following along the plane of the old lumen. The ventral stalk fills with axons while the dorsal tier is shed gradually. In contrast, in the Siamese cat, dorsal stalk cells are not sloughed off properly and instead are incorporated ectopically into the nerve. Basal lamina invagination is irregular. Axons do not fill the Siamese stalk symmetrically but enter the region of ectopic cells, which in turn disrupts gross fiber position. Usually, in the mutant, axons originating from the retina temporal to the optic fissure are those that invade the dorsal tier of ectopic cells. The altered position of optic axons in the mutant stalk may provide an explanation for the chiasmatic misrouting of optic axons in this species.

    View details for Web of Science ID A1988M603300008

    View details for PubMedID 3372729

  • A FIBRONECTIN-LIKE MOLECULE IS PRESENT IN THE DEVELOPING CAT CEREBRAL-CORTEX AND IS CORRELATED WITH SUBPLATE NEURONS JOURNAL OF CELL BIOLOGY CHUN, J. J., Shatz, C. J. 1988; 106 (3): 857-872

    Abstract

    The subplate is a transient zone of the developing cerebral cortex through which postmitotic neurons migrate and growing axons elongate en route to their adult positions within the cortical plate. To learn more about the cellular interactions that occur in this zone, we have examined whether fibronectins (FNs), a family of molecules known to promote migration and elongation in other systems, are present during the fetal and postnatal development of the cat's cerebral cortex. Three different anti-FN antisera recognized a single broad band with an apparent molecular mass of 200-250 kD in antigen-transfer analyses (reducing conditions) of plasma-depleted (perfused) whole fetal brain or synaptosome preparations, indicating that FNs are present at these ages. This band can be detected as early as 1 mo before birth at embryonic day 39. Immunohistochemical examination of the developing cerebral cortex from animals between embryonic day 46 and postnatal day 7 using any of the three antisera revealed that FN-like immunoreactivity is restricted to the subplate and the marginal zones, and is not found in the cortical plate. As these zones mature into their adult counterparts (the white matter and layer 1 of the cerebral cortex), immunostaining gradually disappears and is not detectable by postnatal day 70. Previous studies have shown that the subplate and marginal zones contain a special, transient population of neurons (Chun, J. J. M., M. J. Nakamura, and C. J. Shatz. 1987. Nature (Lond.). 325:617-620). The FN-like immunostaining in the subplate and marginal zone is closely associated with these neurons, and some of the immunostaining delineates them. Moreover, the postnatal disappearance of FN-like immunostaining from the subplate is correlated spatially and temporally with the disappearance of the subplate neurons. When subplate neurons are killed by neurotoxins, FN-like immunostaining is depleted in the lesioned area. These observations show that an FN-like molecule is present transiently in the subplate of the developing cerebral cortex and, further, is spatially and temporally correlated with the transient subplate neurons. The presence of FNs within this zone, but not in the cortical plate, suggests that the extracellular milieu of the subplate mediates a unique set of interactions required for the development of the cerebral cortex.

    View details for Web of Science ID A1988M615800033

    View details for PubMedID 3346327

  • PRENATAL DISRUPTION OF BINOCULAR INTERACTIONS CREATES NOVEL LAMINATION IN THE CATS LATERAL GENICULATE-NUCLEUS VISUAL NEUROSCIENCE Garraghty, P. E., Shatz, C. J., Sur, M. 1988; 1 (1): 93-102

    Abstract

    The elimination of retinogeniculate afferents from one eye on embryonic day 44 (E44) has pronounced effects on the formation of the cellular laminae in the cat lateral geniculate nucleus (LGN). Only two laminae form: a dorsal, "magnocellular" layer, and a ventral, "parvocellular" layer. Soma size measurements and previously reported patterns of termination of retinogeniculate axons suggest that the dorsal lamina is a coalescence of the normal A-laminae and the dorsal, magnocellular division of layer C, while the ventral layer is a composite of the parvocellular sublamina of layer C and the remaining C-laminae. This is a novel pattern of lamination in the LGN that differs from that found in the normal nucleus, not only in that there are now only two cell layers rather than the normal five, but also in that the interlaminar zone occurs in an abnormal location. This result is markedly different from that observed in other species where interlaminar zones present after early monocular enucleation are a subset of the ones which would normally be present. We suggest that, in the absence of ongoing binocular interactions, interactions between functionally distinct retinal ganglion cell classes from the remaining eye may direct the formation of cell laminae in the LGN, even when such interactions are not normally operative.

    View details for Web of Science ID A1988P413000008

    View details for PubMedID 3154791

  • TRANSIENT MORPHOLOGICAL FEATURES OF IDENTIFIED GANGLION-CELLS IN LIVING FETAL AND NEONATAL RETINA SCIENCE Ramoa, A. S., Campbell, G., Shatz, C. J. 1987; 237 (4814): 522-525

    Abstract

    The function and morphology of retinal ganglion cells in the adult mammalian visual system has been well studied, but little is known about how the adult state is achieved. To address this question, the morphological changes that retinal ganglion cells undergo during development were studied. Ganglion cells were first identified by retrograde labeling with rhodamine latex microspheres deposited in retinorecipient targets in fetal and early postnatal cats. The structure of ganglion cells was then revealed by intracellular injection of Lucifer yellow in living retinas removed and maintained in vitro. As early as 2 weeks before birth, a morphologically diverse assortment of ganglion cells is present, some of which resemble the alpha, beta, and gamma classes found in the adult. However, in contrast to the adult, developing ganglion cells exhibit several transient features, including excessive axonal and dendritic branching and exuberant somatic and dendritic spines. These morphological features indicate that there is a transient network of connectivity that could play an important role in the final determination of retinal ganglion cell form and function.

    View details for Web of Science ID A1987J385100028

    View details for PubMedID 3603038

  • TRANSIENT CELLS OF THE DEVELOPING MAMMALIAN TELENCEPHALON ARE PEPTIDE-IMMUNOREACTIVE NEURONS NATURE CHUN, J. J., Nakamura, M. J., Shatz, C. J. 1987; 325 (6105): 617-620

    Abstract

    In the development of the mammalian telencephalon, the genesis of neurons destined for the various layers of the cerebral cortex is preceded by the generation of a population of cells that comes to reside in the subplate and marginal zones (see ref. 2 for nomenclature). In the cat, these cells are present in large numbers during development, when their location is correlated with the arrival and accumulation of ingrowing axonal systems and with synapses. However, as the brain matures, the cells disappear and the white matter and layer 1 of the adult emerge. Their disappearance occurs in concert with the invasion of the cortical plate by the axonal systems and with the elimination of the synapses from the subplate. Here we report that the subplate cells have properties typical of mature neurons. They have the ultrastructural appearance of neurons and receive synaptic contacts. They also have long projections and are immunoreactive for MAP2 (microtubule associated protein 2). Further, subpopulations are immunoreactive for one of several neuropeptides. These observations suggest that during the fetal and early postnatal development of the mammalian telencephalon the subplate cells function as neurons in synaptic circuitry that disappears by adulthood.

    View details for Web of Science ID A1987F973500055

    View details for PubMedID 3543691

  • AXON TRAJECTORIES AND PATTERN OF TERMINAL ARBORIZATION DURING THE PRENATAL DEVELOPMENT OF THE CATS RETINOGENICULATE PATHWAY JOURNAL OF COMPARATIVE NEUROLOGY Sretavan, D. W., Shatz, C. J. 1987; 255 (3): 386-400

    Abstract

    In this study we have examined the trajectories taken by populations of ganglion cell axons and the spatial gradients of terminal arbor maturity within the lateral geniculate nucleus (LGN) during the prenatal development of the cat's visual system. To do so, an in vitro method of labeling optic tract axons from fetal brains between embryonic day 37 (E37) and postnatal day 2 (P2) with horseradish peroxidase (HRP) was used. At the earliest ages studied (E37-E53), optic axons leave the optic tract to run across the LGN toward their sites of termination in straight trajectories parallel to each other. At later ages (E57-P2), however, axons with abrupt changes in their course across the nucleus can be clearly identified. When the detailed terminal arbor morphology of the set of retinogeniculate axons filled with HRP at a given age was examined, two different spatial gradients of maturation could be detected. The terminal arbors of axons within LGN layer A are always more mature than those ending in layer A1, an observation consistent with previous findings that axons from the contralateral eye arrive within the LGN several days before those from the ipsilateral eye. Moreover, the terminal arbors of axons projecting to the medial portions of each layer are always more mature than their more lateral counterparts. These gradients are likely to be a direct reflection of the central-first, peripheral-last gradient associated with the neurogenesis of the retinal ganglion cells themselves. In the oldest animals studied (E58-P2), a remarkable periodic pattern of terminal arbor labeling was seen following a localized HRP injection into the optic tract. Within the labeled portions of the LGN, densely filled axon terminal arbors are separated by unlabeled gaps of similar width. This pattern of labeling could reflect local topographic disorder within the optic tract or could arise if axons of different classes of retinal ganglion cells run in separate portions of the optic tract. Taken together, all of these observations suggest that there may be a fair degree of topographic order in the retinogeniculate projection within the cat's LGN early on in development. However, when topographic errors are present, some can be corrected by minor readjustments in axonal trajectories.

    View details for Web of Science ID A1987F675900005

    View details for PubMedID 3819020

  • Development of the mammalian visual system. Mead Johnson Symposium on Perinatal and Developmental Medicine Shatz, C. J. 1987: 19-26

    View details for PubMedID 3332904

  • THE RELATIONSHIP BETWEEN THE GENICULOCORTICAL AFFERENTS AND THEIR CORTICAL TARGET-CELLS DURING DEVELOPMENT OF THE CATS PRIMARY VISUAL-CORTEX JOURNAL OF NEUROSCIENCE Shatz, C. J., Luskin, M. B. 1986; 6 (12): 3655-3668

    Abstract

    To study the prenatal development of connections between the lateral geniculate nucleus (LGN) and the primary visual cortex in the cat, we have examined the relationship between the position of ingrowing afferents from the LGN and their target cells in cortical layers 4 and 6 at various times during the cat's 65 d gestation period and during the first 3 weeks of postnatal life. In 1 series of experiments, the method of transneuronal transport of intraocularly injected tritiated proline (3H-proline), followed by autoradiography, was used to label the developing geniculocortical pathway. In another series, the tritiated thymidine (3H-thymidine) method was employed to keep track of the cells destined for layers 4 and 6 by labeling them on their birthdates (layer 4: embryonic day (E) 37-43; layer 6: E31-36) (Luskin and Shatz, 1985b) and then charting their locations at subsequent times during development. The results of the 2 sets of experiments were compared at corresponding ages. By E39, many of the cells of cortical layer 6 have completed their migrations and are situated within the cortical plate immediately above the subplate. However, the transneuronal labeling pattern indicates that the geniculocotical afferents have not yet arrived within the vicinity of the future visual cortex, but rather are still en route and confined within the optic radiations of the telencephalon. By E42, a week after the first afferents can be detected in the radiations, substantial transneuronal label is found in the subplate immediately below future visual cortex. However, the overlying cortical plate is free of label. Over the next 2 weeks, geniculocortical axons continue to accumulate in the subplate zone, and, in addition, transneuronal label can be found in the marginal zone. By E55 a faint geniculocortical projection can be detected within the cortical plate, but only within its deeper half (future layers 5 and 6), and even then the major portion of the projection is still confined to the subplate. The absence of a projection to cortical layer 4 at these ages is remarkable in view of the results from our 3H-thymidine experiments, which indicate that by E57 the majority of cells destined to belong to layer 4 have already completed their migrations and assumed positions superficial to the cells of layers 5 and 6. By birth, a substantial geniculocortical projection to cortical layer 4 can be detected in the transneuronal autoradiographs.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1986F314200024

    View details for PubMedID 3794795

  • DEVELOPMENT OF GLUTAMIC-ACID DECARBOXYLASE IMMUNOREACTIVITY IN THE CATS LATERAL GENICULATE-NUCLEUS JOURNAL OF NEUROSCIENCE SHOTWELL, S. L., Shatz, C. J., Luskin, M. B. 1986; 6 (5): 1410-1423

    Abstract

    The development of glutamic acid decarboxylase (GAD) immunoreactivity in the cat's dorsal LGN was studied during fetal and postnatal life. In the adult, inhibitory interactions within the LGN are known to be mediated by GABA. Here we have used an antiserum to GAD, the rate-limiting synthetic enzyme for GABA, to examine the development of the anatomical substrate for this inhibitory system. The pattern of immunostaining observed in the adult cat LGN was similar to that reported by Fitzpatrick et al. (1984), with heavily stained somata and proximal dendrites located within the LGN layers and the adjacent perigeniculate nucleus (PGN). The LGN also contained a complex array of terminal staining. In development, specific staining was seen about 2 weeks before birth and was confined to PGN somata and, to a lesser extent, to somata located in the future ventral C-layers. A similar pattern of immunostaining was seen using GABA antiserum. Not until birth did the A-layers of the LGN show appreciable staining of both somata and terminals; however, even then the pattern of immunostaining was far from mature. Furthermore, excessive numbers of PGN neurons appeared to stain. By 5 weeks after birth, the intensity of both soma and terminal staining within the A-layers of the LGN increased substantially relative to that of the PGN and ventral C-layers. The first glomerular clusters of terminal staining could also be seen, and the number of stained PGN neurons had diminished to levels similar to those seen in the adult. The pattern of immunostaining was almost adultlike by 2 months after birth, except within the C-complex, where the staining did not yet show the distinct difference in staining intensity present in the adult between dorsal layer C and ventral layers C1 and C2. The final adult pattern of GAD immunoreactivity appeared by 3 months after birth. These results suggest that during fetal life the PGN and ventral C-layers of the LGN may supply the first source of GABA-mediated inhibition to the nucleus, with the major portion of the inhibition supplied by intrinsic LGN neurons arising postnatally. Thus, PGN neurons may provide part of the anatomical substrate for the inhibitory interactions seen physiologically during late fetal development (Shatz and Kirkwood, 1984). Finally, the relatively late appearance of the adultlike pattern of GAD immunostaining suggests that intrageniculate inhibitory circuitry continues to develop well after birth.

    View details for Web of Science ID A1986C336000021

    View details for PubMedID 3711986

  • PRENATAL DEVELOPMENT OF CAT RETINOGENICULATE AXON ARBORS IN THE ABSENCE OF BINOCULAR INTERACTIONS JOURNAL OF NEUROSCIENCE Sretavan, D. W., Shatz, C. J. 1986; 6 (4): 990-1003

    Abstract

    During prenatal development of the cat's retinogeniculate projection, inputs from the ganglion cell axons of the two eyes are initially intermixed with each other within the lateral geniculate nucleus (LGN). As development proceeds, the inputs sort out to give rise to the eye-specific layers characteristic of the adult. During this sorting out process, individual axons undergo a stereotyped sequence of morphological changes that ultimately produce the characteristic pattern of arborization in which axon arbors are restricted in extent only to those layers of the LGN appropriate for the eye of origin (Sretavan and Shatz, 1984, 1986). Here, we examine whether binocular interactions between retinal ganglion cell axons from the two eyes are required for the formation of this restricted pattern of terminal arborization. To examine this question, one eye was removed at embryonic day 23 (E23), when ganglion cell axons have not yet reached the optic chiasm, and the ganglion cell axons from the remaining eye were allowed to develop in the complete absence of binocular interactions. At E59, when segregation into eye-specific layers is normally almost complete, the retinogeniculate projection from the remaining eye was then examined both by anterograde transport following intraocular injections of 3H-leucine and by the in vitro filling of individual ganglion cell axons with HRP. Results from the intraocular injections showed that in the absence of one eye, the remaining eye is still capable of forming both ipsilateral and contralateral optic tracts; however, the projection was distributed diffusely throughout each LGN, rather than being confined to normal eye-specific territories. When individual HRP-filled axons were reconstructed and examined, it was remarkable to find that the pattern of terminal arborization was virtually indistinguishable from normal axons. As usual, arbors were restricted to the distal portion of each axon trunk, and measurements showed that the total linear length of axon contributing to each arbor was within the normal range (enucleated, 2310 +/- 920 microns; normal, 2520 +/- 810 microns). Furthermore, the terminal arborizations of axons appeared to be organized into a series of tiers within the LGN in a pattern surprisingly similar to the pattern of eye-specific layers normally present by E59. Also unchanged was the normally occurring loss of axons from the remaining optic nerve: Counts at E59 showed that about 2.3 X 10(5) axons were present in enucleated animals as compared to 2.5 X 10(5) axons in controls.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1986A967600011

    View details for PubMedID 3701418

  • PRENATAL DEVELOPMENT OF RETINAL GANGLION-CELL AXONS - SEGREGATION INTO EYE-SPECIFIC LAYERS WITHIN THE CATS LATERAL GENICULATE-NUCLEUS JOURNAL OF NEUROSCIENCE Sretavan, D. W., Shatz, C. J. 1986; 6 (1): 234-251

    Abstract

    The morphological changes in individual retinal ganglion cell axons associated with the formation of the eye-specific layers in the dorsal lateral geniculate nucleus (LGN) were studied during the prenatal development of the cat's visual system. Previous work has shown that the pattern of segregated eye inputs found in the adult arises from an immature state in which inputs from the two eyes are intermixed within the nucleus (Shatz, 1983). Here, this developmental process is examined at its fundamental unit of connectivity--the individual retinal ganglion cell axon. To do so, an in vitro method was used to label fetal cat optic tract axons with HRP at various times during development between embryonic day 38 (E38) and postnatal day 2 (P2) (gestation = 65 d). The results presented here are based on reconstructions of 172 axons. During the initial period of intermixing (E38-43), axons are relatively simple in morphology. Many axons studied at the earliest ages (E38) end in growth cones and have very few branches along the main axon trunk as they traverse the nucleus. By E43, the number of side branches given off along the main axon trunk has increased and most axons also have a simple terminal arbor. Over the next 2 weeks (E43-55), the majority of axons are studded with side branches and the terminal arbor is well defined. Then, between E55 and birth, axons lose their side branches and the eye-specific layers appear. By birth, nearly all axons have a smooth trunk and an elaborate terminal arbor restricted to the LGN layer appropriate to the eye of axon origin. When the number of side branches per axon was quantified, the time course of appearance and subsequent loss of side branches was found to parallel the time course of the initial intermixing of inputs and subsequent reduction in territory shared by the two eyes as determined from previous intraocular injection experiments. Our results also showed that the side branches along each axon were located primarily within LGN territory destined to be occupied by the other eye. Thus, the side branches are likely to represent a morphological substrate for the intermixing of inputs from the two eyes. These observations suggest that the segregation of eye input to the LGN involves two fundamental and simultaneous events. One event is the remodeling of the branching pattern along the length of the main axon trunk so that the side branches present early on are eliminated and the main axon trunk becomes smooth.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1986A567600025

    View details for PubMedID 3944621

  • INTERACTIONS BETWEEN RETINAL GANGLION-CELLS DURING THE DEVELOPMENT OF THE MAMMALIAN VISUAL-SYSTEM ANNUAL REVIEW OF NEUROSCIENCE Shatz, C. J., Sretavan, D. W. 1986; 9: 171-207

    View details for Web of Science ID A1986A575000008

    View details for PubMedID 2423004

  • NEUROGENESIS OF THE CATS PRIMARY VISUAL-CORTEX JOURNAL OF COMPARATIVE NEUROLOGY Luskin, M. B., Shatz, C. J. 1985; 242 (4): 611-631

    Abstract

    The 3H-thymidine method of birth-dating was used to determine when the cells belonging to each of the principal cellular layers of the cat's primary visual cortex are generated. In order to detect systematic differences in the position of radioactively labeled cells following 3H-thymidine administration at different prenatal ages, a geometric method was devised to represent the distribution of labeled cells in the form of depth histograms. Results show that visual cortical neurogenesis occurs largely during the second half of gestation between embryonic day 31 (E31) and E57. Cells of layer 6 are generated early, between E31 and E38, whereas cells destined for successively more superficial layers are generated at progressively later times. Layer 4 cells, the principal targets of geniculocortical afferents, are generated between E37 and E44. In addition, a special population of cells embedded in the white matter below layer 6 was found to be produced throughout the week-long period immediately prior to the onset of layer 6 neurogenesis. Overall, this radial pattern of cortical neurogenesis closely resembles the inside-first, outside-last, spatiotemporal sequence of development described for the monkey's primary visual cortex (Rakic, '74). In addition to finding this pronounced gradient in the radial dimension, we were also able to detect a less pronounced gradient along the tangential dimension: neurons destined for any given layer in the anterior part of the cortex (inferior visual field representation) are generated slightly in advance of neurons destined for more posterior regions (superior visual field). However even our more quantitative histogram analysis failed to reveal a mediolateral (central to peripheral visual field) gradient within area 17. In the cat, layers 6, 5, and 4 each take about a week to be generated, although their total cell numbers and packing densities differ in the adult. About 2 weeks are required to produce the cells of layers 2 and 3 combined. Furthermore, we found that neurons belonging to different layers and different morphological classes can be generated simultaneously. This suggests that the identity of a cortical neuron is not solely a function of the time of neurogenesis.

    View details for Web of Science ID A1985AXP8400008

    View details for PubMedID 4086673

  • Visual neurobiology: development of visual pathways in mammals. Science Shatz, C. J. 1985; 228 (4695): 67-68

    View details for PubMedID 17811567

  • ABNORMAL-DEVELOPMENT OF THE RETINOGENICULATE PROJECTION IN SIAMESE CATS JOURNAL OF NEUROSCIENCE Kliot, M., Shatz, C. J. 1985; 5 (10): 2641-2653

    Abstract

    In the visual system of Siamese cats, the lateral geniculate nucleus (LGN) receives an abnormally large projection from the contralateral eye and a correspondingly reduced projection from the ipsilateral eye. In order to determine how this abnormal pattern of retinal input arises, the prenatal development of the retinogeniculate projection was studied in Siamese cats using the anterograde transport of intraocularly injected [3H]leucine and horseradish peroxidase. Labeled axons from the ipsilateral eye can be detected in the optic tract by embryonic day 30 (E30; gestation is 65 days), several days later than found in normally pigmented animals. The ipsilateral projection is not only apparently delayed but also is reduced in size as compared with normal animals, and this reduction persists throughout development, indicating that the Siamese mutation acts to misdirect growing optic axons to the contralateral side of the brain as originally proposed (Guillery, R. W. (1969) Brain Res. 14: 739-741). The effect of an altered retinal projection on the ingrowth and segregation of retinal fibers to the LGN was also examined. In Siamese fetuses, not until E41 can significant label be seen within the ipsilateral LGN as compared to E35 in normally pigmented fetuses. As in normal animals, in Siamese fetuses, also, the labeled retinogeniculate afferents from the two eyes initially overlap within regions of the LGN before segregating into layers. However, measurements of the area occupied by labeled afferents from the ipsilateral and contralateral eyes indicate that maximum overlap of the two sets of afferents, although close to normal in amount, does not occur until about E51--again several days later than in normally pigmented animals (E47). The time course of segregation is also altered in Siamese cats. The onset of segregation, as signaled by the removal of contralateral eye afferents from territory destined for the ipsilateral eye and by the restriction of ipsilateral eye afferents, does not occur until about E51 in Siamese cats as compared with E47 in normally pigmented animals. Despite this delay in onset, the final segregation of the two sets of afferents in Siamese cats reaches adult-like levels at about the normal time. Thus, the misrouting of axons at the optic chiasm in Siamese cats not only alters the final pattern of innervation from the two eyes within the LGN, but also delays the onset and shortens the total duration of segregation itself.

    View details for Web of Science ID A1985ASM4200008

    View details for PubMedID 2995604

  • STUDIES OF THE EARLIEST GENERATED CELLS OF THE CATS VISUAL-CORTEX - COGENERATION OF SUBPLATE AND MARGINAL ZONES JOURNAL OF NEUROSCIENCE Luskin, M. B., Shatz, C. J. 1985; 5 (4): 1062-1075

    Abstract

    The earliest generated cells of the cat's telencephalon that may play a role in the formation of the primary visual cortex are the subject of this study. Using [3H]thymidine autoradiography, we have found that these cells are generated between embryonic day 24 (E24) and E30 (gestation is 65 days) and that they are present in very low numbers in the white matter of the adult brain. These cells are rarely labeled by injections made after E30, when the cells destined for the cortical layers are generated. Examination of the labeling pattern in the fetal brain 10 days or more after administration of [3H]thymidine between E24 and E30 revealed a bistratified distribution of these early generated cells. Labeled cells were found in large numbers in two embryonic zones flanking the developing cortical plate: above in the marginal zone and below in the subplate. (Some if not all of the marginal zone cells constitute the population of Cajal-Retzius cells of the cat's telencephalon.). These experiments indicate that cells of the subplate and marginal zones are cogenerated in time during the days just preceding the genesis of the cortical plate. We also examined the distribution of the early generated cells shortly after their genesis--on E30, a time when cells of the cortical plate are just being generated at the ventricular zone. In this case, the labeling pattern at the occipital pole was not bistratified. Rather, labeled cells were situated within a single zone extending from the pial surface inward to the border of the ventricular zone. This finding indicates that the cells of the subplate and marginal zones are generated as a contiguous population that is subsequently split apart by the insertion of cells forming the cortical plate. A comparison between the number of early generated cells found in fetal and newborn brains with that found in adult brains suggests that these cells are generated initially in substantial numbers but then largely disappear during early postnatal life, since injections of [3H]thymidine between E24 and E30 yielded large numbers of labeled cells in the white matter and layer 1 at birth, but very few at 2 months postnatal. This significant loss contrasted with the results from injections made just a few days later (E33) that resulted in large numbers of labeled cells in cortical layer 6 not only at birth but also in adulthood.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1985AFN9800024

    View details for PubMedID 3981242

  • PRENATAL DEVELOPMENT OF INDIVIDUAL RETINOGENICULATE AXONS DURING THE PERIOD OF SEGREGATION NATURE Sretavan, D., Shatz, C. J. 1984; 308 (5962): 845-848

    Abstract

    When connections are first formed during the development of the vertebrate nervous system, inputs from different sources are frequently intermixed and the specific adult pattern then emerges as the different inputs segregate from each other. During the prenatal development of connections between retina and lateral geniculate nucleus (LGN) in the cat, the projections from the two eyes initially overlap with each other within the LGN. Over the next 3 weeks a reduction in the amount of overlap occurs so that by birth, a segregated pattern similar to the adult is present. We report here that during the period of overlap, individual retinogeniculate axons are simple in shape and restricted in extent without any widespread branches. Further, the appearance of the segregated pattern of eye input is accompanied by the elaboration of extensive new axonal arbors within appropriate LGN territory accompanied by retraction of only a limited number of minor branches. This developmental strategy contrasts with that in other regions of the vertebrate central nervous system in which the orderly adult pattern of connections within a target is achieved by a relative reduction in the overall extent of the axon arbor.

    View details for Web of Science ID A1984SN80100080

    View details for PubMedID 6201743

  • PRENATAL DEVELOPMENT OF FUNCTIONAL CONNECTIONS IN THE CATS RETINOGENICULATE PATHWAY JOURNAL OF NEUROSCIENCE Shatz, C. J., Kirkwood, P. A. 1984; 4 (5): 1378-1397

    Abstract

    The development of functional connections between the axons of retinal ganglion cells and the neurons of the dorsal lateral geniculate nucleus (LGNd) of fetal and neonatal cats was studied using an in vitro assay. Extracellular microelectrode recordings of single units were made from histologically identified sites in the LGNd of isolated diencephalon preparations between embryonic day 39 ( E39 ) and postnatal day 2 (P2). (Gestation is 65 days in the cat.) Postsynaptic units activated by electrical stimulation of one or both optic nerves were found at all ages tested from E39 onwards. Over 90% of the units studied in the fetal preparations received convergent excitation from both optic nerves, compared with roughly half of the units studied in the neonatal optic nerves, compared with roughly half of the units studied in the neonatal preparations. Inhibition was detected in the LGNd of the neonatal preparations, but in only the oldest of the fetal preparations ( E59 ). This physiological change from predominantly convergent excitation to an adult-like mixture of excitation and inhibition seen at birth coincides with the change from mixed to segregated afferent input from the two eyes seen anatomically ( Shatz , C. J. (1983) J. Neurosci . 3: 482-499). These results indicate that attainment of the adult pattern of retinogeniculate connectivity involves the elimination of already functional synapses.

    View details for Web of Science ID A1984ST87900023

    View details for PubMedID 6726337

  • THE PRENATAL DEVELOPMENT OF THE CATS RETINOGENICULATE PATHWAY JOURNAL OF NEUROSCIENCE Shatz, C. J. 1983; 3 (3): 482-499

    Abstract

    The prenatal development of connections between the retina and the lateral geniculate nucleus (LGN) was studied by means of the anterograde axonal transport of 3H-amino acids or horseradish peroxidase injected intraocularly in fetal cats older than embryonic day 27 (E27) and in newborn cats. (Gestation is 65 days.) A retinothalamic pathway exists as early as E28, when label can be seen in both ipsilateral and contralateral optic tracts. Afferents from the contralateral eye are the first to invade the anlage of the LGN by E32 with those from the ipsilateral eye following about 3 days later. Initially, the pattern of labeling within the nucleus is uniform, suggesting that the two sets of afferents must share a good deal of territory at early ages. By E47, however, gaps appear in the labeling pattern contralaterally, indicating that afferents from the two eyes are beginning to segregate from each other. Segregation continues so that by E54 it is possible to identify unambiguously regions of the LGN destined to comprise ipsilateral and contralateral eye layers. By birth, afferent input appears adult-like in organization, with the two sets of afferents almost completely segregated from each other into their appropriate layers. Cellular lamination of the nucleus has just commenced, however, thereby lagging the onset of afferent segregation by about 2 weeks. Prenatal development could be followed much more easily in the horizontal than in the coronal plane of section due to the finding here that the LGN is displaced approximately 90 degrees in the horizontal plane between E40 and E60. Measurements of the area occupied by the ipsilateral and contralateral afferents within the LGN indicated that even prior to segregation, the two sets of afferents are not completely intermixed within the LGN. On the contrary, those from the contralateral eye retain almost exclusive control of some territory throughout development. This detail contrasts with development in primates, in which intermixing of afferents from the two eyes is thought to be complete early on (Rakic, P. (1976) Nature 261: 467-471). Nevertheless, in the cat, as in other mammals, development of the retinogeniculate pathway is broadly characterized by an initial period of overlap followed by a period of segregation that gives rise to the adult pattern of afferent input.

    View details for Web of Science ID A1983QG96000004

    View details for PubMedID 6402566

  • PRENATAL MISROUTING OF THE RETINOGENICULATE PATHWAY IN SIAMESE CATS NATURE Shatz, C. J., Kliot, M. 1982; 300 (5892): 525-529

    View details for Web of Science ID A1982PT23900047

    View details for PubMedID 7144904

  • THE GENESIS OF EFFERENT CONNECTIONS FROM THE VISUAL-CORTEX OF THE FETAL RHESUS-MONKEY JOURNAL OF COMPARATIVE NEUROLOGY Shatz, C. J., RAKIC, P. 1981; 196 (2): 287-307

    Abstract

    The prenatal development of the cortical projections to the dorsal lateral geniculate nucleus (LGN), superior colliculus (SC) and pulvinar was studied by autoradiography of orthogradely transported 3H-proline injected into the occipital cortex of fetal rhesus monkeys aged from embryonic day 63 (E63) to E95. Differentiation of pyramidal neurons situated in the infragranular strata of the cortical plate (prospective layers 5 and 6, which give rise to these efferent projections) was also examined in Golgi preparations prepared from specimens of corresponding embryonic ages. In autoradiographs of the E63 fetus, no radioactive label was seen in subcortical structures. In two specimens injected around E70, label was present in the prospective magnocellular layers of the LGN and within the immediately surrounding cell-poor zones. At these young fetal ages, the presence of topographic order in the corticogeniculate projection could not be determined due to the large size of the injection sites relative to the small cerebral vesicles. By E84 the portion of the prospective parvocellular layers adjacent to the white matter also contained label which was characteristically wedge-shaped and appropriately located with respect to the site of the cortical injection, suggesting that topographic order is established. In the oldest fetus (E95) label in the LGN assumed a configuration similar to that seen in the adult. The cortical projection also invades the SC and pulvinar around E70. In the SC, label was initially confined to the stratum opticum, but by E84 it extended into the superficial gray. Thus, all known classes of efferent pathways from the visual cortex to subcortical structures are present by the middle of the 165-day gestational period in rhesus monkey. The one-month period, E63-E97, during which these efferent visual connections are established is characterized by the considerable growth and increased complexity of the dendritic arborization of pyramidal cells in the infragranular cortical layers of area 17. Thus the development of visual cortical efferents occurs in rough synchrony with the genesis of the afferent pathway from the LGN (Rakic, '76a; '79) and with the onset of morphological differentiation of pyramidal neurons in the infragranular cortical layers.

    View details for Web of Science ID A1981LE95900007

    View details for PubMedID 7217358

  • SIAMESE CAT - ALTERED CONNECTIONS OF VISUAL-CORTEX SCIENCE Shatz, C. J., LeVay, S. 1979; 204 (4390): 328-330

    Abstract

    In siamese cats, each side of the brain receives a retinal input serving part of the ipsilateral visual field as well as the normal contralateral field representation. Both corticothalamic and cortico-cortical projections are systematically rearranged, but while one is retinotopically appropriate, the other fails to make a distinction between ipsilateral and contralateral fields. Different rules appear to govern the development of these two sets of connections.

    View details for Web of Science ID A1979GR21300037

    View details for PubMedID 432647

  • OCULAR DOMINANCE COLUMNS AND THEIR DEVELOPMENT IN LAYER 4 OF CATS VISUAL-CORTEX - QUANTITATIVE STUDY JOURNAL OF COMPARATIVE NEUROLOGY LeVay, S., Stryker, M. P., Shatz, C. J. 1978; 179 (1): 223-244

    View details for Web of Science ID A1978ES62800012

    View details for PubMedID 8980725

  • OCULAR DOMINANCE IN LAYER-IV OF CATS VISUAL-CORTEX AND EFFECTS OF MONOCULAR DEPRIVATION JOURNAL OF PHYSIOLOGY-LONDON Shatz, C. J., Stryker, M. P. 1978; 281 (AUG): 267-?

    Abstract

    1. The relation between the physiological pattern of ocular dominance and the anatomical distribution of geniculocortical afferents serving each eye was studied in layer IV of the primary visual cortex of normal and monocularly deprived cats. 2. One eye was injected with radioactive label. After allowing sufficient time for transeuronal transport, micro-electrode recordings were made, and the geniculocoritcal afferents serving the injected eye were located autoradiographically. 3. In layer IV of normal cats, cell were clustered according to eye preference, and fewer cells were binocularly driven than in other layers. Points of transition between groups of cells dominated by one eye and those dominated by the other were marked with electrolytic lesions. A good correspondence was found between the location of cells dominated by the injected eye and the patches of radioactively labelled geniculocortical afferents. 4. Following prolonged early monocular deprivation, the patches of geniculocortical afferents in layer IV serving the deprived eye were smaller, and those serving the non-deprived eye larger, than normal. Again there was a coincidence between the patches of radioactively labelled afferents and the location of cells dominated by the injected eye. 5. The deprived eye was found to dominate a substantial fraction (22%) of cortical cells in the fourth layer. In other cortical layers, only 7% of the cells were dominated by the deprived eye. 6. These findings suggest that the thalamocortical projection is physically rearranged as a consequence of monocular deprivation, as has been demonstrated for layer IVc of the monkey's visual cortex (Hubel, Wiesel & Le Vay, 1977).

    View details for Web of Science ID A1978FP25200017

    View details for PubMedID 702379

  • ANATOMY OF INTERHEMISPHERIC CONNECTIONS IN VISUAL-SYSTEM OF BOSTON SIAMESE AND ORDINARY CATS JOURNAL OF COMPARATIVE NEUROLOGY Shatz, C. J. 1977; 173 (3): 497-518

    Abstract

    In Siamese cats, previous studies have shown that a genetic mutation causes retinogeniculate fibers in each eye which arise from the temporal retina representing the 20 degrees of ipsilateral visual field adjacent to the vertical meridian to cross aberrantly in the optic chiasm, thereby terminating in the wrong lateral geniculate nucleus. The abnormality is expressed subsequently at the level of the visual cortex. This paper presents anatomical evidence that the pattern of commissural visual connections in the "Boston" variety of Siamese cat also is highly abnormal in comparison to that of ordinary cats. The topographical distribution of neurons supplying visual fibers to the splenium of the corpus callosum was studied in Boston Siamese and ordinary cats using the method of retrograde transport of horseradish peroxidase (HRP) following localized cortical injections made through a recording micropipette. In ordinary cats, after an HRP injection at the border between cortical areas 17 and 18, which represents the vertical meridian of the visual field, HRP-labeled cells in areas 17 and 18 of the opposite hemisphere were found only immediately adjacent to the 17-18 border, thus confirming the results of previous investigations. In Boston Siamese cats, the border represents a region in the ipsilateral visual field roughly 20 degrees away from the vertical meridian, and the vertical meridian representation is displaced to sites within areas 17 and 18 proper. When HRP was injected at the 17-18 border, labeled cells in the opposite hemisphere were located well within area 17 near the suprasplenial sulcus, and also well within area 18; few labeled cells were found at the 17-18 border. When an HRP injection was placed at the vertical meridian representation, again few HRP-labeled cells were found at the opposite 17-18 border, but instead most were found in area 17 slightly medial to the border, and in area 18 slightly lateral to it. Thee findings were complemented in an autoradiographic study in which orthograde transport of tritiated proline after a localized cortical injection was used to demonstrate the distribution of callosal terminals. Thus the pattern of callosal connections revealed in Boston Siamese cats, although anatomically different from that of ordinary cats, was nevertheless consistent with the proposal that cortical sites representing similar visual field coordinates in each hemisphere are appropriately interconnected via the corpus callosum. The laminar distribution of callosal connections was examined briefly. Layer III pyramidal cells of areas 17 and 18 supplied the majority of terminals to the opposite 17-18 border. Pyramidal cells of Layers II and VI, and Layer IVa in area 18, made a smaller contribution. In areas 17 and 18, the same cortical layers (II, III, and VI; and IVa in 18) were again the major sites of callosal termination. A clear projection to the base of layer I was also noted. The laminar distribution of callosal connections in ordinary and Boston Siamese cats were not substantially different.

    View details for Web of Science ID A1977DC83100006

    View details for PubMedID 856894

  • DISTRIBUTION OF AFFERENTS REPRESENTING RIGHT AND LEFT EYES IN CATS VISUAL-CORTEX BRAIN RESEARCH Shatz, C. J., Lindstrom, S., Wiesel, T. N. 1977; 131 (1): 103-116

    View details for Web of Science ID A1977DQ83300007

    View details for PubMedID 884538

Conference Proceedings


  • Emergence of order in visual system development Shatz, C. J. NATL ACAD SCIENCES. 1996: 602-608

    Abstract

    Neural connections in the adult central nervous system are highly precise. In the visual system, retinal ganglion cells send their axons to target neurons in the lateral geniculate nucleus (LGN) in such a way that axons originating from the two eyes terminate in adjacent but nonoverlapping eye-specific layers. During development, however, inputs from the two eyes are intermixed, and the adult pattern emerges gradually as axons from the two eyes sort out to form the layers. Experiments indicate that the sorting-out process, even though it occurs in utero in higher mammals and always before vision, requires retinal ganglion cell signaling; blocking retinal ganglion cell action potentials with tetrodotoxin prevents the formation of the layers. These action potentials are endogenously generated by the ganglion cells, which fire spontaneously and synchronously with each other, generating "waves" of activity that travel across the retina. Calcium imaging of the retina shows that the ganglion cells undergo correlated calcium bursting to generate the waves and that amacrine cells also participate in the correlated activity patterns. Physiological recordings from LGN neurons in vitro indicate that the quasiperiodic activity generated by the retinal ganglion cells is transmitted across the synapse between ganglion cells to drive target LGN neurons. These observations suggest that (i) a neural circuit within the immature retina is responsible for generating specific spatiotemporal patterns of neural activity; (ii) spontaneous activity generated in the retina is propagated across central synapses; and (iii) even before the photoreceptors are present, nerve cell function is essential for correct wiring of the visual system during early development. Since spontaneously generated activity is known to be present elsewhere in the developing CNS, this process of activity-dependent wiring could be used throughout the nervous system to help refine early sets of neural connections into their highly precise adult patterns.

    View details for Web of Science ID A1996TR32600013

    View details for PubMedID 8570602

  • SUBPLATE NEURONS AND THE DEVELOPMENT OF NEOCORTICAL CONNECTIONS Shatz, C. J., Ghosh, A., McConnell, S. K., Allendoerfer, K. L., FRIAUF, E., Antonini, A. M I T PRESS. 1991: 175-196

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