John R. Huguenard






		John R. Huguenard Title Associate Professor Department Neurology and Neurological Sciences Research Interests Neuronal mechanisms of oscillatory activity in the thalamocortical system, especially in relation to cognition, sleep and epilepsy. In vitro neurophysiological and in silico computational approaches are used. Email John.Huguenard@stanford.edu Phone 723-5522 Fax 723-1080 Address Alway M016 Mail Code: 5122 Faculty Research Description What are the neuronal mechanisms that underlie network synchrony in the thalamus, cortex and the massively interconnected thalamocortical system? Such oscillations are related to cognitive processes, normal sleep activities and certain forms of epilepsy. Our approach is an analysis of the discrete components that make up thalamic and cortical circuits, and reconstitution of components into both in vitro biological and in silico computational networks. Accordingly, we have been able to identify genes whose products, mainly ion channels, play key roles in the regulation of thalamocortical network responses. Currently, projects focus on: Development of excitatory connections in neocortex, with an emphasis on AMPA receptor alterations in the early postnatal period -- Molecular pharmacology of inhibitory GABA-A receptors in the thalamus -- and the role of receptor phosphorylation in regulating inhibitory function -- Analysis of progression and destabilization of widespread thalamic network activity using large microelectrode arrays -- The roles of neuropeptides, especially NPY, SST, and VIP in regulating thalamic and cortical function -- Reorganization of neocortical connectivity following injury -- Roles of specific GABA-B receptors in regulating pre- and postsynaptic function. The laboratory uses experimental techniques ranging from biophysical studies of single ion channels to in vivo recording to purely theoretical studies of network synchrony. Our toolbox includes: --Use of mutant mouse models for analysis of gene function in circuit behavior. For example, knockout and knockin mice have been used to identify the specific GABA-A receptor isoforms that are critical for the therapeutic actions of benzodiazepines in thalamus -- patch clamp recording methods for single channels and whole cell currents, with both isolated neurons and those in situ in brain slices -- multi-unit, multi-site extracellular recording techniques -- immunohistochemical techniques for cell identification and protein localization -- molecular & genetic approaches for in situ hybridization of specific transcripts -- targeted antisense oligodeoxynucleotide knockdown of specific gene products -- microscopic techniques for computerized neuronal reconstruction (Neurolucida) -- laser uncaging of photo-labile glutamate derivatives for circuit analysis -- single cell intracellular perfusion for modification of e.g., phosphorylation state -- paired intracellular recordings for analysis of single-axon synaptic connections -- fluorometric detection of calcium indicator dyes in cells and circuits -- local perfusion within slice micro-regions for pharmacological analysis -- computer-based modeling of single cell and circuit behaviors. Representative Publication(s): Kumar, S.S., Bacci, A., Kharazia, V. and Huguenard, J.R. (2002) A developmental switch of AMPA-receptor subunits in neocortical pyramidal neurons. J. Neurosci., In Press Porcello, D.M., Ho, C.S., Joho, R.H and Huguenard, J.R. (2002) Subtle deficits in RTN neuronal firing patterns of Kv3.1 deficient mice suggests genetic redundancy in fast action potential repolarization mechanisms. J. Neurophysiol. In Press. Huntsman, M.M., Porcello, D.M., Homanics, G.E., DeLorey, T.M. and Huguenard, J.R. (1999) Reciprocal inhibitory connections and network synchrony in the mammalian thalamus. Science. 283:541-543. Sohal, V.S. and Huguenard, J.R. (1998) Long-range connections synchronize rather than spread intrathalamic oscillatory activity: computational modeling and in vitro electrophysiology. J. Neurophysiol. 80:1736-1751. Xiang, Z., Huguenard, J.R. and Prince, D.A. (1998) Cholinergic switching within neocortical inhibitory networks. Science. 281:985-988. Areas of Study Systems/Behavioral Neuroscience Cellular Neurobiology Membrane Excitability Developmental Neuroscience SBRC Ph.D.