Geoffrey Kerchner

Journal Articles

• APOE {varepsilon}4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory. Neurology Kerchner, G. A., Berdnik, D., Shen, J. C., Bernstein, J. D., Fenesy, M. C., Deutsch, G. K., Wyss-Coray, T., Rutt, B. K. 2014; 82 (8): 691-697

  Abstract

  Using high-resolution structural MRI, we endeavored to study the relationships among APOE ε4, hippocampal subfield and stratal anatomy, and episodic memory.Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE ε4 carrier status. Each subject underwent ultra-high-field 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment.We found a selective, dose-dependent association of APOE ε4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in Alzheimer disease. The relationship between the ε4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE ε4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers. In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE ε4 allele to its phenotypic effects on memory.The APOE ε4 allele segregated dose-dependently and selectively with CA1-SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation.

  View details for DOI 10.1212/WNL.0000000000000154

  View details for PubMedID 24453080

• Shared vulnerability of two synaptically-connected medial temporal lobe areas to age and cognitive decline: a seven tesla magnetic resonance imaging study. journal of neuroscience Kerchner, G. A., Bernstein, J. D., Fenesy, M. C., Deutsch, G. K., Saranathan, M., Zeineh, M. M., Rutt, B. K. 2013; 33 (42): 16666-16672

  Abstract

  The medial temporal lobe (MTL) is the first brain area to succumb to neurofibrillary tau pathology in Alzheimer's disease (AD). Postmortem human tissue evaluation suggests that this pathology propagates in an ordered manner, with the entorhinal cortex (ERC) and then CA1 stratum radiatum and stratum lacunosum-moleculare (CA1-SRLM)-two monosynaptically connected structures-exhibiting selective damage. Here, we hypothesized that, if ERC and CA1-SRLM share an early vulnerability to AD pathology, then atrophy should occur in a proportional manner between the two structures. We tested this hypothesis in living humans, using ultra-high field 7.0 T MRI to make fine measurements of MTL microstructure. Among a pool of age-matched healthy controls and patients with amnestic mild cognitive impairment and mild AD, we found a significant correlation between ERC and CA1-SRLM size that could not be explained by global atrophy affecting the MTL. Of the various structures that contribute axons or dendrites into the CA1-SRLM neuropil, only ERC emerged as a significant predictor of CA1-SRLM size in a linear regression analysis. In contrast, other synaptically connected elements of the MTL did not exhibit size correlations. CA1-SRLM and ERC structural covariance was significant for older controls and not patients, whereas the opposite pattern emerged for a correlation between CA1-SRLM and episodic memory performance. Interestingly, CA1-SRLM and ERC were the only MTL structures to atrophy in older controls relative to a younger comparison group. Together, these findings suggest that ERC and CA1-SRLM share vulnerability to both age and AD-associated atrophy.

  View details for DOI 10.1523/JNEUROSCI.1915-13.2013

  View details for PubMedID 24133269

• Influenza-associated global amnesia and hippocampal imaging abnormality. Neurocase Lopez, J., Lomen-Hoerth, C., Deutsch, G. K., Kerchner, G. A., Koshy, A. 2013

  Abstract

  The acute phase of influenza infection is rarely associated with significant cognitive dysfunction. We describe a case of a 24 year-old man who developed global amnesia in the acute phase of influenza A infection. His deficits resolved over the course of several weeks. Transient abnormalities of diffusion and T2-weighted imaging were seen in the bilateral hippocampi. We review cerebral complications of influenza and discuss the possible role of previously proposed mechanisms in our patient's case.

  View details for PubMedID 23697757

• Novel presenilin-1 Y159F sequence variant associated with early-onset Alzheimer's disease NEUROSCIENCE LETTERS Kerchner, G. A., Holbrook, K. 2012; 531 (2): 142-144

  Abstract

  Mutations in the gene for presenilin-1 cause familial, early-onset Alzheimer's disease.We report the case of a 43-year-old woman presenting with progressive cognitive decline and a family history of early-onset dementia. Her workup included cerebrospinal fluid amyloid-beta, tau, and phospho-tau levels, as well as genetic sequencing of genes implicated in familial Alzheimer's disease.Cerebrospinal fluid biomarkers were consistent with a diagnosis of Alzheimer's disease. A novel nucleotide sequence variant (A476T) was discovered in one allele for presenilin-1, corresponding to a missense tyrosine-to-phenylalanine change at codon 159 (Y159F). An affected maternal uncle carried the same allele. The sequence variant occurs in a conserved region of the gene near other previously reported mutations.This novel presenilin-1 sequence variant cosegregated with early onset dementia in the proband and at least one other affected family member, and likely represents a mutation causing familial, early-onset Alzheimer's disease.

  View details for DOI 10.1016/j.neulet.2012.10.037

  View details for Web of Science ID 000312612800016

  View details for PubMedID 23123781

• Cognitive Processing Speed in Older Adults: Relationship with White Matter Integrity PLOS ONE Kerchner, G. A., Racine, C. A., Hale, S., Wilheim, R., Laluz, V., Miller, B. L., Kramer, J. H. 2012; 7 (11)

  Abstract

  Cognitive processing slows with age. We sought to determine the importance of white matter integrity, assessed by diffusion tensor imaging (DTI), at influencing cognitive processing speed among normal older adults, assessed using a novel battery of computerized, non-verbal, choice reaction time tasks. We studied 131 cognitively normal adults aged 55-87 using a cross-sectional design. Each participant underwent our test battery, as well as MRI with DTI. We carried out cross-subject comparisons using tract-based spatial statistics. As expected, reaction time slowed significantly with age. In diffuse areas of frontal and parietal white matter, especially the anterior corpus callosum, fractional anisotropy values correlated negatively with reaction time. The genu and body of the corpus callosum, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus were among the areas most involved. This relationship was not explained by gray or white matter atrophy or by white matter lesion volume. In a statistical mediation analysis, loss of white matter integrity mediated the relationship between age and cognitive processing speed.

  View details for DOI 10.1371/journal.pone.0050425

  View details for Web of Science ID 000311821000234

  View details for PubMedID 23185621

• Hippocampal CA1 apical neuropil atrophy and memory performance in Alzheimer's disease NEUROIMAGE Kerchner, G. A., Deutsch, G. K., Zeineh, M., Dougherty, R. F., Saranathan, M., Rutt, B. K. 2012; 63 (1): 194-202

  Abstract

  Memory loss is often the first and most prominent symptom of Alzheimer's disease (AD), coinciding with the spread of neurofibrillary pathology from the entorhinal cortex (ERC) to the hippocampus. The apical dendrites of hippocampal CA1 pyramidal neurons, in the stratum radiatum/stratum lacunosum-moleculare (SRLM), are among the earliest targets of this pathology, and atrophy of the CA1-SRLM is apparent in postmortem tissue from patients with mild AD. We previously demonstrated that CA1-SRLM thinning is also apparent in vivo, using ultra-high field 7-Tesla (7T) MRI to obtain high-resolution hippocampal microstructural imaging. Here, we hypothesized that CA1-SRLM thickness would correlate with episodic memory performance among patients with mild AD. We scanned nine patients, using an oblique coronal T2-weighted sequence through the hippocampal body with an in-plane resolution of 220 ?m, allowing direct visual identification of subfields - dentate gyrus (DG)/CA3, CA2, CA1, and ERC - and hippocampal strata - SRLM and stratum pyramidale (SP). We present a novel semi-automated method of measuring stratal width that correlated well with manual measurements. We performed multi-domain neuropsychological evaluations that included three tests of episodic memory, yielding composite scores for immediate recall, delayed recall, and delayed recognition memory. Strong correlations occurred between delayed recall performance and the widths of CA1-SRLM (r(2)=0.69; p=0.005), CA1-SP (r(2)=0.5; p=0.034), and ERC (r(2)=0.62; p=0.012). The correlation between CA1-SRLM width and delayed recall lateralized to the left hemisphere. DG/CA3 size did not correlate significantly with any aspect of memory performance. These findings highlight a role for 7T hippocampal microstructural imaging in revealing focal structural pathology that correlates with the central cognitive feature of AD.

  View details for DOI 10.1016/j.neuroimage.2012.06.048

  View details for Web of Science ID 000308770300020

  View details for PubMedID 22766164

• From Alois to Amyvid Seeing Alzheimer disease NEUROLOGY Furst, A. J., Kerchner, G. A. 2012; 79 (16): 1628-1629

  View details for DOI 10.1212/WNL.0b013e3182662084

  View details for Web of Science ID 000309991800005

  View details for PubMedID 22786589

• A 44-Year-Old Man with Profound Behavioural Changes CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES Laforce, R., Kerchner, G. A., Rabinovici, G. D., Fong, J. C., Miller, B. L., Seeley, W. W., Grinberg, L. T. 2012; 39 (4): 527-530

  View details for Web of Science ID 000307090400020

  View details for PubMedID 22728864

• Amyloid imaging for Alzheimer's disease. Expert opinion on medical diagnostics Kerchner, G. A. 2011; 5 (6): 527-538

  Abstract

  Introduction: Biomarkers for Alzheimer's disease (AD) may facilitate early and accurate diagnosis and offer a way to track the effectiveness of new therapies. Amyloid imaging offers an unrivaled ability to visualize the presence and anatomical distribution of fibrillar beta-amyloid (Aβ) pathology non-invasively in living humans. New diagnostic criteria for AD incorporate the use of such biomarkers as amyloid imaging, highlighting the importance of this technology going forward. Areas covered: Here, the author reviews individual amyloid tracers, including the (11)C-labeled tracer Pittsburgh compound B and the (18)F-labeled tracers nearing FDA approval. While these tracers are reliable at detecting fibrillar Aβ pathology, there is a weaker connection with true AD pathology, reflecting the complex relationship between Aβ and AD. The author discusses apolipoprotein E genotyping and spinal fluid Aβ levels in relation to amyloid imaging, and considers the possible uses of amyloid imaging as a diagnostic instrument in the clinic, or as a clinical trials tool for selecting patients or monitoring outcomes. Selected literature retrieved by Medline searches for 'amyloid imaging' and related terms from 2001 to present is discussed. Expert opinion: Amyloid imaging accurately portrays the presence of fibrillar Aβ pathology in the brain. However, fundamental questions about the role of Aβ in AD must be answered before the full potential of amyloid imaging can be realized.

  View details for DOI 10.1517/17530059.2011.617365

  View details for PubMedID 23484750

• Abhorring the vacuum: use of Alzheimer's disease medications in frontotemporal dementia EXPERT REVIEW OF NEUROTHERAPEUTICS Kerchner, G. A., Tartaglia, M. C., Boxer, A. L. 2011; 11 (5): 709-717

  Abstract

  There is no dedicated therapy for frontotemporal dementia (FTD). In order to treat the often devastating behavioral disturbances that interfere with both normal social functioning and the ability of caregivers to provide needed support, off-label medication usage is frequent. In addition to antidepressant and antipsychotic medications, which afford some benefits, US FDA-approved treatments for Alzheimer's disease are often used, including both cholinesterase inhibitors and memantine. Here, we review the various clinical manifestations of FTD, a general approach to treatment and the goals of any potential therapies. We review all of the existing literature on the use of cholinesterase inhibitors and memantine in FTD. While cholinesterase inhibitors do not currently have a place in FTD treatment, memantine may be helpful, although the results of two placebo-controlled trials with this agent are not yet available. Finally, we discuss our view that such approaches will probably become supplanted by rational, molecularly-based therapies currently in development.

  View details for DOI 10.1586/ERN.11.6

  View details for Web of Science ID 000290834200015

  View details for PubMedID 21728274

• Ultra-High Field 7T MRI: A New Tool for Studying Alzheimer's Disease JOURNAL OF ALZHEIMERS DISEASE Kerchner, G. A. 2011; 26: 91-95

  Abstract

  Ultra-high field 7T MRI offers superior signal-to-noise and spatial resolution relative to any other noninvasive imaging technique. By revealing fine anatomical details of the living brain, 7T MRI allows neuroimaging researchers the opportunity to observe in patients disease-related structural changes previously apparent only on postmortem tissue analysis. Alzheimer's disease (AD) is a natural subject for this technology, and I review here two AD-related applications of 7T MRI: direct visualization of cortical plaques, and high resolution hippocampal imaging. I also discuss limitations of this technology as well as expected advances that are likely to establish 7T MRI as an increasingly important tool for the diagnosis and tracking of AD.

  View details for DOI 10.3233/JAD-2011-0023

  View details for Web of Science ID 000297842800006

  View details for PubMedID 21971453

• Hippocampal CA1 apical neuropil atrophy in mild Alzheimer disease visualized with 7-T MRI NEUROLOGY Kerchner, G. A., Hess, C. P., Hammond-Rosenbluth, K. E., Xu, D., Rabinovici, G. D., Kelley, D. A., Vigneron, D. B., Nelson, S. J., Miller, B. L. 2010; 75 (15): 1381-1387

  Abstract

  In Alzheimer disease (AD), mounting evidence points to a greater role for synaptic loss than neuronal loss. Supporting this notion, multiple postmortem studies have demonstrated that the hippocampal CA1 apical neuropil is one of the earliest sites of pathology, exhibiting tau aggregates and then atrophy before there is substantial loss of the CA1 pyramidal neurons themselves. In this cross-sectional study, we tested whether tissue loss in the CA1 apical neuropil layer can be observed in vivo in patients with mild AD.We performed ultra-high-field 7-T MRI on subjects with mild AD (n = 14) and age-matched normal controls (n = 16). With a 2-dimensional T2*-weighted gradient-recalled echo sequence that was easily tolerated by subjects, we obtained cross-sectional slices of the hippocampus at an in-plane resolution of 195 ?m.On images revealing the anatomic landmarks of hippocampal subfields and strata, we observed thinning of the CA1 apical neuropil in subjects with mild AD compared to controls. By contrast, the 2 groups exhibited no difference in the thickness of the CA1 cell body layer or of the entire CA1 subfield. Hippocampal volume, measured on a conventional T1-weighted sequence obtained at 3T, also did not differentiate these patients with mild AD from controls.CA1 apical neuropil atrophy is apparent in patients with mild AD. With its superior spatial resolution, 7-T MRI permits in vivo analysis of a very focal, early site of AD pathology.

  View details for Web of Science ID 000282884500015

  View details for PubMedID 20938031

• Bapineuzumab EXPERT OPINION ON BIOLOGICAL THERAPY Kerchner, G. A., Boxer, A. L. 2010; 10 (7): 1121-1130

  Abstract

  Alzheimer's disease is the leading cause of dementia in the elderly, and there is no disease-modifying therapy yet available. Immunotherapy directed against the beta-amyloid peptide may be capable of slowing the rate of disease progression. Bapineuzumab, an anti-beta-amyloid monoclonal antibody, will be the first such agent to emerge from Phase III clinical trials.The primary literature on bapineuzumab from 2009 and 2010 is reviewed in its entirety, along with the literature on AN1792, a first-generation anti-beta-amyloid vaccine, from 2003 to 2009. Other Alzheimer's disease immunotherapeutics currently in development, according to www.clinicaltrials.gov , are also discussed.In addition to a critical appraisal of the Phase II trial results for bapineuzumab, this review considers the broader field of immunotherapy for Alzheimer's disease as a whole, including the challenges ahead.Bapineuzumab appears capable of reducing the cerebral beta-amyloid peptide burden in patients with Alzheimer's disease. However, particularly in APOE 4 carriers, its ability to slow disease progression remains uncertain, and vasogenic edema - a dose-limiting and potentially severe adverse reaction - may limit its clinical applicability.

  View details for DOI 10.1517/14712598.2010.493872

  View details for Web of Science ID 000280190800010

  View details for PubMedID 20497044

• Critical role for TARPs in early development despite broad functional redundancy NEUROPHARMACOLOGY Menuz, K., Kerchner, G. A., O'Brien, J. L., Nicoll, R. A. 2009; 56 (1): 22-29

  Abstract

  Transmembrane AMPA receptor regulatory proteins (TARPs), including gamma-2, gamma-3, gamma-4, and gamma-8, are auxiliary subunits for AMPA receptors. Based on studies in single knockout mice, it has been suggested that nearly all native AMPA receptors are associated with TARPs. To study the interplay between TARP family members and AMPA receptors in vivo, we generated mice lacking multiple TARPs. Triple knockout mice lacking gamma-3, gamma-4, and gamma-8 are viable and fertile, and synaptic AMPA receptor activity is reduced to a level comparable to that seen in gamma-8 single knockout mice. In contrast, triple knockout mice lacking gamma-2, gamma-3, and either gamma-4 or gamma-8 cannot survive ex utero. In particular, gamma-2, gamma-3, gamma-4 triple knockout mice are born apneic and paralyzed, despite normal AMPA receptor function in cortical and spinal neurons. We found that gamma-8 is expressed at low levels in early postnatal mice and regulates AMPA receptor levels at this developmental time period. Thus, the early expression of gamma-8 may be responsible for maintaining AMPA receptor functions in neonatal neurons. Together, our data indicate that TARPs, in particular gamma-2, are essential for early development, and that most neurons express multiple members of this functionally redundant protein family.

  View details for DOI 10.1016/j.neuropharm.2008.06.037

  View details for Web of Science ID 000262625500004

  View details for PubMedID 18634809

• Silent synapses and the emergence of a postsynaptic mechanism for LTP NATURE REVIEWS NEUROSCIENCE Kerchner, G. A., Nicoll, R. A. 2008; 9 (11): 813-825

  Abstract

  Silent synapses abound in the young brain, representing an early step in the pathway of experience-dependent synaptic development. Discovered amidst the debate over whether long-term potentiation reflects a presynaptic or a postsynaptic modification, silent synapses--which in the hippocampal CA1 subfield are characterized by the presence of NMDA receptors but not AMPA receptors--have stirred some mechanistic controversy of their own. Out of this literature has emerged a model for synapse unsilencing that highlights the central role for postsynaptic AMPA-receptor trafficking in the expression of excitatory synaptic plasticity.

  View details for DOI 10.1038/nrn2501

  View details for Web of Science ID 000260184000013

  View details for PubMedID 18854855

• Co-occurrence of a cavernous malformation and contralateral moyamoya NEUROLOGY Kerchner, G. A., Smith, W., Lawton, M. T., Singh, V. 2006; 66 (10): 1601-1602

  View details for Web of Science ID 000237706900038

  View details for PubMedID 16717235

• Kainate receptor subunits underlying presynaptic regulation of transmitter release in the dorsal horn JOURNAL OF NEUROSCIENCE Kerchner, G. A., Wilding, T. J., Huettner, J. E., Zhuo, M. 2002; 22 (18): 8010-8017

  Abstract

  Presynaptic kainate (KA) receptors regulate synaptic transmission at both excitatory and inhibitory synapses in the spinal cord dorsal horn. Previous work has demonstrated pharmacological differences between the KA receptors expressed by rat dorsal horn neurons and those expressed by the primary afferent sensory neurons that innervate the dorsal horn. Here, neurons isolated from KA receptor subunit-deficient mice were used to evaluate the contribution of glutamate receptor subunit 5 (GluR5) and GluR6 to the presynaptic control of transmitter release and to KA receptor-mediated whole-cell currents in these two cell populations [corrected]. Deletion of GluR6 produced a significant reduction in KA receptor-mediated current density in dorsal horn neurons, whereas GluR5 deletion caused no change in current density but removed sensitivity to GluR5-selective antagonists. Presynaptic modulation of inhibitory transmission between dorsal horn neurons was preserved in cells from either GluR5- or GluR6-deficient mice. In DRG neurons, in contrast, GluR5 deletion abolished KA receptor function, whereas deletion of GluR6 had little effect on peak current density but increased the rate and extent of desensitization. These results highlight fundamental differences in KA receptor physiology between the two cell types and suggest possible strategies for the pharmacological modulation of nociception.

  View details for Web of Science ID 000177916000021

  View details for PubMedID 12223554

• Presynaptic suppression of dorsal horn inhibitory transmission by mu-opioid receptors JOURNAL OF NEUROPHYSIOLOGY Kerchner, G. A., Zhuo, M. 2002; 88 (1): 520-522

  Abstract

  Opioids modify sensory experience at many levels in the CNS. The mechanisms of this action, including the ways opioid receptors affect synaptic transmission, are not yet fully understood. Here we show that the selective activation of mu-opioid receptors suppressed inhibitory transmission between spinal cord dorsal horn neurons in vitro. mu-Opioid receptor activation reduced evoked inhibitory postsynaptic current (eIPSC) amplitude by acting presynaptically, because it altered the paired-pulse ratio, did not affect GABA-evoked currents, and decreased miniature IPSC (mIPSC) frequency. The mechanism of this effect was independent both of presynaptic Ca(2+) entry and of the pathway linking presynaptic kainate (KA) receptors to suppression of inhibitory transmission in the same cells. These data identify mu-opioid receptors as important presynaptic modulators of dorsal horn inhibitory transmission.

  View details for DOI 10.1152/jn.01053.2001

  View details for Web of Science ID 000176493800048

  View details for PubMedID 12091574

• Glutamate and the presynaptic control of spinal sensory transmission NEUROSCIENTIST Huettner, J. E., Kerchner, G. A., Zhuo, M. 2002; 8 (2): 89-92

  Abstract

  Sensory neurons, in particular the small- and medium-diameter cells that sense painful stimuli, express both ionotropic and metabotropic glutamate receptors, which may regulate transmission between sensory neurons and their targets in the spinal cord dorsal horn. Although the roles that these receptors play in normal physiology are not completely understood, recent work has provided strong evidence for their ability to modulate transmitter release from primary afferent terminals.

  View details for Web of Science ID 000174679600009

  View details for PubMedID 11954562

• Direct presynaptic regulation of GABA/glycine release by kainate receptors in the dorsal horn: An ionotropic mechanism NEURON Kerchner, G. A., Wang, G. D., Qiu, C. S., Huettner, J. E., Zhuo, M. 2001; 32 (3): 477-488

  Abstract

  In the spinal cord dorsal horn, excitatory sensory fibers terminate adjacent to interneuron terminals. Here, we show that kainate (KA) receptor activation triggered action potential-independent release of GABA and glycine from dorsal horn interneurons. This release was transient, because KA receptors desensitized, and it required Na+ entry and Ca2+ channel activation. KA modulated evoked inhibitory transmission in a dose-dependent, biphasic manner, with suppression being more prominent. In recordings from isolated neuron pairs, this suppression required GABA(B) receptor activation, suggesting that KA-triggered GABA release activated presynaptic GABA(B) autoreceptors. Finally, glutamate released from sensory fibers caused a KA and GABA(B) receptor-dependent suppression of inhibitory transmission in spinal slices. Thus, we show how presynaptic KA receptors are linked to changes in GABA/glycine release and highlight a novel role for these receptors in regulating sensory transmission.

  View details for Web of Science ID 000172119100013

  View details for PubMedID 11709158

• Do 'smart' mice feel more pain, or are they just better learners? Reply NATURE NEUROSCIENCE Kerchner, G. A., Wei, F., Wang, G. D., Kim, S. J., Xu, H. M., Robinson, D. A., Li, P., Chen, Z. F., Zhuo, M. 2001; 4 (5): 453-454

  View details for Web of Science ID 000168412600003

• Genetic enhancement of inflammatory pain by forebrain NR2B overexpression NATURE NEUROSCIENCE Wei, F., Wang, G. D., Kerchner, G. A., Kim, S. J., Xu, H. M., Chen, Z. F., Zhuo, M. 2001; 4 (2): 164-169

  Abstract

  N-methyl-D-aspartate (NMDA) receptors contribute to many brain functions. We studied the effect of forebrain-targeted overexpression of the NMDA receptor subunit NR2B on the response of mice to tissue injury and inflammation. Transgenic mice exhibited prominent NR2B expression and enhanced NMDA receptor-mediated synaptic responses in two pain-related forebrain areas, the anterior cingulate cortex and insular cortex, but not in the spinal cord. Although transgenic and wild type mice were indistinguishable in tests of acute pain, transgenic mice exhibited enhanced responsiveness to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant. Genetic modification of forebrain NMDA receptors can therefore influence pain perception, which suggests that forebrain-selective NMDA receptor antagonists, including NR2B-selective agents, may be useful analgesics for persistent pain.

  View details for Web of Science ID 000167178100015

  View details for PubMedID 11175877

• Presynaptic kainate receptors regulate spinal sensory transmission JOURNAL OF NEUROSCIENCE Kerchner, G. A., Wilding, T. J., Li, P., Zhuo, M., Huettner, J. E. 2001; 21 (1): 59-66

  Abstract

  Small diameter dorsal root ganglion (DRG) neurons, which include cells that transmit nociceptive information into the spinal cord, are known to express functional kainate receptors. It is well established that exposure to kainate will depolarize C-fiber afferents arising from these cells. Although the role of kainate receptors on sensory afferents is unknown, it has been hypothesized that presynaptic kainate receptors may regulate glutamate release in the spinal cord. Here we show that kainate, applied at low micromolar concentrations in the presence of the AMPA-selective antagonist (RS)-4-(4-aminophenyl)-1, 2-dihydro-1-methyl-2-propyl-carbamoyl-6,7-methylenedioxyphthalazine++ +, suppressed spontaneous NMDA receptor-mediated EPSCs in cultures of spinal dorsal horn neurons. In addition, kainate suppressed EPSCs in dorsal horn neurons evoked by stimulation of synaptically coupled DRG cells in DRG-dorsal horn neuron cocultures. Interestingly, although the glutamate receptor subunit 5-selective kainate receptor agonist (RS)-2-alpha-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA) (2 micrometer) was able to suppress DRG-dorsal horn synaptic transmission to a similar extent as kainate (10 micrometer), it had no effect on excitatory transmission between dorsal horn neurons. Agonist applications revealed a striking difference between kainate receptors expressed by DRG and dorsal horn neurons. Whereas DRG cell kainate receptors were sensitive to both kainate and ATPA, most dorsal horn neurons responded only to kainate. Finally, in recordings from dorsal horn neurons in spinal slices, kainate and ATPA were able to suppress NMDA and AMPA receptor-mediated EPSCs evoked by dorsal root fiber stimulation. Together, these data suggest that kainate receptor agonists, acting at a presynaptic locus, can reduce glutamate release from primary afferent sensory synapses.

  View details for Web of Science ID 000166278500011

  View details for PubMedID 11150320

• Zn2+ current is mediated by voltage-gated Ca2+ channels and enhanced by extracellular acidity in mouse cortical neurones JOURNAL OF PHYSIOLOGY-LONDON Kerchner, G. A., Canzoniero, L. M., Yu, S. P., Ling, C., Choi, D. W. 2000; 528 (1): 39-52

  Abstract

  1. Mammalian neuronal voltage-gated Ca2+ channels have been implicated as potential mediators of membrane permeability to Zn2+. We tested directly whether voltage-gated Ca2+ channels can flux Zn2+ in whole-cell voltage-clamp recordings from cultured murine cortical neurones. 2. In the presence of extracellular Zn2+ and no Na+, K+, or other divalent cations, a small, non-inactivating, voltage-gated inward current was observed exhibiting a current-voltage relationship characteristic of high-voltage activated (HVA) Ca2+ channels. Inward current was detectable at Zn2+ levels as low as 50 microM, and both the amplitude and voltage sensitivity of the current depended upon Zn2+ concentration. This Zn2+ current was sensitive to blockade by Gd3+ and nimodipine and, to a lesser extent, by omega-conotoxin GVIA. 3. Zn2+ could permeate Ca2+ channels in the presence of Ca2+ and other physiological cations. Inward currents recorded with 2 mM Ca2+ were attenuated by Zn2+ (IC50 = 210 microM), and currents recorded with Zn2+ were unaffected by up to equimolar Ca2+ concentrations. Furthermore, the Zn2+-selective fluorescent dye Newport Green revealed a depolarisation-activated, nimodipine-sensitive Zn2+ influx into cortical neurones that were bathed in a physiological extracellular solution plus 300 microM ZnCl2. 4. Surprisingly, while lowering extracellular pH suppressed HVA Ca2+ currents, Zn2+ current amplitude was affected oppositely, varying inversely with pH with an apparent pK of 7.4. The acidity-induced enhancement of Zn2+ current was associated with a positive shift in reversal potential but no change in the kinetics or voltage sensitivity of channel activation. 5. These results provide evidence that L- and N-type voltage-gated Ca2+ channels can mediate Zn2+ entry into cortical neurones and that this entry may be enhanced by extracellular acidity.

  View details for Web of Science ID 000089949400007

  View details for PubMedID 11018104

• Zinc-induced neuronal death in cortical neurons CELLULAR AND MOLECULAR BIOLOGY Lobner, D., Canzoniero, L. M., Manzerra, P., Gottron, F., Ying, H., Knudson, M., Tian, M., Dugan, L. L., Kerchner, G. A., Sheline, C. T., Korsmeyer, S. J., Choi, D. W. 2000; 46 (4): 797-806

  Abstract

  Although Zn2+ is normally stored and released in the brain, excessive exposure to extracellular Zn2+ can be neurotoxic. The purpose of the present study was to determine the type of neuronal cell death, necrosis versus apoptosis, induced by Zn2+ exposure. Addition of 10-50 microM ZnCl2 to the bathing medium of murine neuronal and glial cell cultures induced, over the next 24 hrs., Zn2+-concentration-dependent neuronal death; some glial death also occurred with Zn2+ concentrations above 30 microM. The neuronal death induced by 20 microM Zn2+ was characterized by coarse chromatin condensation, the formation of apoptotic bodies, and internucleosomal DNA fragmentation. It was attenuated in cortical cell cultures prepared from mice null for the bax gene, and by the caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-CH2F (ZVAD, 100 microM), but not by the NMDA receptor antagonist, D-2-amino-5-phosphonovalerate (D-APV, 200 microM ). In contrast, the neuronal death induced by 50 microM Zn2+ was characterized by plasma membrane disruption and random DNA fragmentation; this death was attenuated by D-APV, but exhibited little sensitivity to ZVAD or deletion of bax. These results suggest that Zn2+ can induce cell death with characteristics of either apoptosis or necrosis, depending on the intensity of the Zn2+ exposure.

  View details for Web of Science ID 000087633700010

  View details for PubMedID 10875441

• AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses NATURE NEUROSCIENCE Li, P., Kerchner, G. A., Sala, C., Wei, F., Huettner, J. E., Sheng, M., Zhuo, M. 1999; 2 (11): 972-977

  Abstract

  Silent synapses form between some primary sensory afferents and dorsal horn neurons in the spinal cord. Molecular mechanisms for activation or conversion of silent synapses to conducting synapses are unknown. Serotonin can trigger activation of silent synapses in dorsal horn neurons by recruiting AMPA receptors. AMPA-receptor subunits GluR2 and GluR3 interact via their cytoplasmic C termini with PDZ-domain-containing proteins such as GRIP (glutamate receptor interacting protein), but the functional significance of these interactions is unclear. Here we demonstrate that protein interactions involving the GluR2/3 C terminus are important for serotonin-induced activation of silent synapses in the spinal cord. Furthermore, PKC is a necessary and sufficient trigger for this activation. These results implicate AMPA receptor-PDZ interactions in mechanisms underlying sensory synaptic potentiation and provide insights into the pathogenesis of chronic pain.

  View details for Web of Science ID 000083883300013

  View details for PubMedID 10526335

• Genetic enhancement of learning and memory in mice NATURE Tang, Y. P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G. S., Tsien, J. Z. 1999; 401 (6748): 63-69

  Abstract

  Hebb's rule (1949) states that learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active. This implies that enhanced synaptic coincidence detection would lead to better learning and memory. If the NMDA (N-methyl-D-aspartate) receptor, a synaptic coincidence detector, acts as a graded switch for memory formation, enhanced signal detection by NMDA receptors should enhance learning and memory. Here we show that overexpression of NMDA receptor 2B (NR2B) in the forebrains of transgenic mice leads to enhanced activation of NMDA receptors, facilitating synaptic potentiation in response to stimulation at 10-100 Hz. These mice exhibit superior ability in learning and memory in various behavioural tasks, showing that NR2B is critical in gating the age-dependent threshold for plasticity and memory formation. NMDA-receptor-dependent modifications of synaptic efficacy, therefore, represent a unifying mechanism for associative learning and memory. Our results suggest that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible.

  View details for Web of Science ID 000082374400041

  View details for PubMedID 10485705

• Speaking out of turn: A role for silent synapses in pain IUBMB LIFE Kerchner, G. A., Li, P., Zhuo, M. 1999; 48 (3): 251-256

  Abstract

  Severe tissue or nerve injury can result in a chronic and inappropriate sensation of pain, mediated in part by the sensitization of spinal dorsal horn neurons to input from primary afferent fibers. Synaptic transmission at primary afferent synapses is mainly glutamatergic. Although a functioning excitatory synapse contains both alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the postsynaptic membrane, recent evidence suggests that dorsal horn neurons contain some "silent" synapses, which exhibit purely NMDA receptor-mediated evoked postsynaptic currents and do not conduct signals at resting membrane potential. Serotonin, which is released onto dorsal horn neurons by descending fibers from the rostroventral medulla, potentiates sensory transmission by activating silent synapses on those neurons, i.e., by recruiting functional AMPA receptors to the postsynaptic membrane. This phenomenon may contribute to the hyperexcitability of dorsal horn neurons seen in chronic pain conditions.

  View details for Web of Science ID 000084128300002

  View details for PubMedID 10690634

• Zinc-mediated neuronal death after transient global ischemia PHARMACOLOGY OF CEREBRAL ISCHEMIA 1998 Choi, D. W., Sheline, C. T., Kerchner, G. A., Majid, A., Canzoniero, L. M. 1999: 173-176

  View details for Web of Science ID 000082191900017

• Endogenous voltage-gated potassium channels in human embryonic kidney (HEK293) cells JOURNAL OF NEUROSCIENCE RESEARCH Yu, S. P., Kerchner, G. A. 1998; 52 (5): 612-617

  Abstract

  Endogenous voltage-gated potassium currents were investigated in human embryonic kidney (HEK293) and Chinese hamster ovary (CHO) cells using whole-cell voltage clamp recording. Depolarizing voltage steps from -70 mV triggered an outwardly rectified current in nontransfected HEK293 cells. This current had an amplitude of 296 pA at +40 mV and a current density of 19.2 pA/pF. The outward current was eliminated by replacing internal K+ with Cs+ and suppressed by the K+ channel blockers tetraethylammonium and 4-aminopyridine. Raising external K+ attenuated the outward current and shifted the reversal potential towards positive potentials as predicted by the Nernst equation. The current had a fast activation phase but inactivated slowly. These features implicate delayed rectifier (I(K))-like channels as mediators of the observed current, which was comparable in size to I(K) currents in many other cells. A small native inward rectifier current but no transient outward current I(A), the M current I(M), or Ca2+-dependent K+ currents were detected in HEK293 cells. In contrast to these findings in HEK293 cells, little or no I(K)-like current was detected in CHO cells. The difference in endogenous voltage-activated currents in HEK293 and CHO cells suggest that CHO cell lines are a preferred system for exogenous K+ channel expression.

  View details for Web of Science ID 000073900300013

  View details for PubMedID 9632317

• Measurement of intracellular free zinc in living cortical neurons: Routes of entry JOURNAL OF NEUROSCIENCE Sensi, S. L., Canzoniero, L. M., Yu, S. P., Ying, H. S., Koh, J. Y., Kerchner, G. A., Choi, D. W. 1997; 17 (24): 9554-9564

  Abstract

  We used the ratioable fluorescent dye mag-fura-5 to measure intracellular free Zn2+ ([Zn2+]i) in cultured neocortical neurons exposed to neurotoxic concentrations of Zn2+ in concert with depolarization or glutamate receptor activation and identified four routes of Zn2+ entry. Neurons exposed to extracellular Zn2+ plus high K+ responded with a peak cell body signal corresponding to a [Zn2+]i of 35-45 nM. This increase in [Zn2+]i was attenuated by concurrent addition of Gd3+, verapamil, omega-conotoxin GVIA, or nimodipine, consistent with Zn2+ entry through voltage-gated Ca2+channels. Furthermore, under conditions favoring reverse operation of the Na+-Ca2+ exchanger, Zn2+ application induced a slow increase in [Zn2+]i and outward whole-cell current sensitive to benzamil-amiloride. Thus, a second route of Zn2+ entry into neurons may be via transporter-mediated exchange with intracellular Na+. Both NMDA and kainate also induced rapid increases in neuronal [Zn2+]i. The NMDA-induced increase was only partly sensitive to Gd3+ or to removal of extracellular Na+, consistent with a third route of entry directly through NMDA receptor-gated channels. The kainate-induced increase was highly sensitive to Gd3+ or Na+ removal in most neurons but insensitive in a minority subpopulation ("cobalt-positive cells"), suggesting that a fourth route of neuronal Zn2+ entry is through the Ca2+-permeable channels gated by certain subtypes of AMPA or kainate receptors.

  View details for Web of Science ID A1997YK82200016

  View details for PubMedID 9391010