Stanford University Epilepsy Training Program

Postdoctoral Epilepsy Training Program Stanford University

Postdoctoral trainees: Qualifications, criteria

Examples of recent publications involving trainees

Overview: The institutional postdoctoral training program in neuroscience and epilepsy allows faculty in the Departments of Biological Sciences, Molecular and Cellular Physiology, Comparative Medicine, Neurology and Neurological Sciences, Neurobiology, and Psychiatry at Stanford University to attract fellows to careers in research areas ultimately relevant to the problems of epilepsy in man. The program, supported by a grant from the NINDS as well as other gift and grant funds, has been in place for 20 years and provided training for a large number of fellows who have become faculty involved in independent NIH-funded academic programs at Stanford and other institutions.. The faculty listed below employ the methods of cellular neurophysiology and biophysics, biochemistry, molecular biology, neuroanatomy, neuropharmacology, and the use of animal model systems for studies of normal and abnormal structure/function. Faculty research interests include cortical neuronal and glial development; physiological and morphological changes in nerve cells and circuits in animal models of chronic neocortical and hippocampal epileptogenesis; effects of drugs and transmitters on neurons and network activity in cortex and thalamus; development, organization, and synaptic physiology of the cerebral cortex; cellular and molecular aspects of long-term changes in neuronal excitability; the role of gene structure, expression and modulation on neuronal function; the role of intracellular second messengers and kinases in coordination of neuronal function; and the effects of trophic factors in the normal and diseased nervous system. Trainees may learn techniques of neurophysiology and neuropharmacology applied to neurons in slices or cultures, including patch-clamp methods for biophysical studies and assessment of transmitter actions; use of in vivo and in vitro animal models of epileptogenesis; anatomic techniques for intracellular labeling, immunocytochemistry and in situ hybridization; cell culture; molecular techniques including gene isolation and cloning, site directed mutagenesis; cell transplantation; experimental gene therapy; and use of transgenic animals. A variety of available courses and seminars contribute to the breadth of research training. Participation of clinical department faculty fosters effective research interactions between MD and PhD trainees and a focus on the interface between basic neuroscience and clinical issues requiring investigation. Applicants are solicited in accord with, and in the spirit of affirmative action.

Involved Departments and Faculty: Training takes place in the laboratories of the faculty within the Departments of Biological Sciences, Molecular and Cellular Physiology, Comparative Medicine, Neurobiology, Neurology and Neurological Sciences and Psychiatry and Behavioral Sciences at Stanford University, Stanford, California. Trainees in these laboratories also have access to various core facilities. Faculty include those listed below:

· John Huguenard, Ph.D. Neurology & Neurological Sciences, Program Director

· Ben Barres, M.D. Ph.D. Neurobiology

· Paul Buckmaster, DVM, Ph.D. Comparative Medicine

· Robert Fisher, MD, Ph.D. Neurology & Neurological Sciences

· Eric I. Knudsen, Ph.D. Professor of Neurobiology

· Liqun Luo, Ph.D. Biological Sciences

· Daniel Madison, Ph.D. Molecular & Cellular Physiology

· Robert Malenka, M.D., Ph.D. Psychiatry & Behavioral Sciences

· William Mobley, M.D., Ph.D. Neurology & Neurological Sciences

· Susan McConnell, Ph.D. Biological Sciences

· David Prince, M.D. Neurology & Neurological Sciences

· Richard Reimer, M.D. Neurology & Neurological Sciences

· Robert Sapolsky, Ph.D. Biological Sciences

Ben Barres, M.D., PhD., Professor of Neurobiology, Neurology and Neurological Sciences and Developmental Biology: Dr. Barres is interested in the development and function of glial cells in the mammalian central nervous system. To understand the interactions between neurons and glial cells he has developed methods to highly purify and culture retinal ganglion cells (neurons) as well as the glial cell types they interact with, oligodendrocytes and astrocytes, from the rodent optic nerve. Barres and his fellows have used a large variety of methods to address these issues including cell purification by immunopanning, tissue culture, patch clamping, immunohistochemistry and molecular biology. Currently, they are focusing on several questions: (1) What are the cell-cell interactions that control myelination and node of Ranvier formation? (2) Do glial cells play a role in synapse formation and function? (3) What are the signals that promote the survival and growth of retinal ganglion cells; can this knowledge be used to promote their survival and regeneration after injury? (4) How do protoplasmic astrocytes, the main glial cell type in gray matter, develop and what is their function? Dr. Barres has found evidence for several novel glial signals that induce the onset of myelination, the clustering of axonal sodium channels, the survival and growth of retinal ganglion cells, and the formation of synapses. He is characterizing these processes and attempting to identify the glial-derived molecules.

Paul Buckmaster, D.V.M., Ph.D., Assistant Professor of Comparative Medicine: Dr. Buckmaster works on problems of hippocampal anatomy, physiology and experimental epilepsy. His major research goal is to understand the basic cellular mechanisms of epileptogenesis. His laboratory uses electrophysiological, molecular, and anatomical methods to examine the neuronal circuitry in rodent models of epilepsy. Current projects are focused on synaptic reorganization in the hippocampal dentate gyrus, changes in GABAergic circuitry in the dentate gyrus and entorhinal cortex, and molecular mechanisms of hyperexcitability in a model of inherited epilepsy. Trainees in Dr. Buckmaster's laboratory will learn a variety of electrophysiological and neuroanatomical techniques including in vivo intracellular recording and labeling, three-dimensional neuron reconstruction, whole-cell voltage-clamp recording, EEG and unit recording, quantitative PCR, in situ hybridization, immunocytochemistry, confocal microscopy, electron microscopy, and stereological methods.

Robert S. Fisher, MD PhD (New Training Faculty) Dr. Fisher is Maslah Saul MD Professor of Neurology and Director of the Stanford Comprehensive Epilepsy Center. He received his Ph.D. in the Neurosciences in 1976 and an M.D. in 1977, from Stanford University. He then took specialty training in internal medicine at Stanford and in neurology at Johns Hopkins, where he was Co-Director of the Epilepsy Program for eleven years. He formerly was Chairman of the Department of Neurology, Chief of the Epilepsy Center at Barrow Neurological Institute in Phoenix, and Newsome Professor of Clinical Neurology at the University of Arizona. Dr. Fisher is author or co-author of over 120 peer-reviewed publications in medical journals, two books on epilepsy and two monographs. He frequently chairs symposia and meetings, speaks at national or international conferences on subjects related to seizure disorders, has been on review boards for national grant applications, and currently serves on the editorial board of several epilepsy and EEG-related journals. He has won research awards from the Klingenstein Foundation, the Epilepsy Foundation of America and the National Institutes of Health. His peers named him to be listed 1996-2003 in Best Doctors in America. Dr. Fisher has served in numerous positions in the epilepsy community, including as President of the American Epilepsy Society, and current Editor-in-Chief of the Journal, Epilepsia. Dr. Fisher s research is on mechanisms of acquired absence epilepsy, studied in the rat and mouse thalamic slice and in vivo. He is investigating a model produced by block of cholesterol synthesis in baby rats, leading to long-term absence seizures and spike-wave EEG patterns. Studies indicate reactive changes in benzodiazepine receptors, and perhaps in certain calcium channels. Dr. Fisher also studies new technologies for treating intractable seizures, with an emphasis on translational research. He has been the main force behind recent laboratory and clinical studies of thalamic stimulation for epilepsy, and he is the pioneer in originating techniques for direct drug application to the seizure focus.

John Huguenard, Ph.D., Associate Professor of Neurology and Neurological Sciences: Current research directions in Dr. Huguenard's laboratory include regulation of excitability in thalamic neurons and the interactions between voltage- and ligand-gated conductances in single neurons within the thalamic and cortical circuits. This approach has led to insights regarding how genetic defects can lead to the hyperexcitability that causes epilepsy. His biophysical studies of low threshold calcium currents and their modulation by selective petit mal anticonvulsants, as well as experiments dealing with effects of benzodiazepines and ethosuximide on thalamic neurons and circuits have important implications for both the mechanisms and potential therapies of epilepsies in which spike-wave discharges are prominent features. Dr. Huguenard has also been involved in studies of development of voltage-dependent conductances in cortical neurons. An in vitro callosal slice preparation has recently been developed as a model of intracortical excitatory connectivity for the purposes of exploring its developmental and neuromodulatory regulation. Mouse knockouts are used to define the roles of specific molecules (ion channels) in complex neuronal functions. Modeling is an important tool in the laboratory, useful in the integration of neurophysiological data and generation of hypotheses. Trainees in his laboratory will learn techniques for studying biophysics of voltage- and ligand-gated currents in neurons utilizing mainly in vitro slice preparations, circuit mapping via UV laser molecular uncaging, dynamic clamp, and computer simulation tools (NEURON). There are currently 6 fellows in Dr. Huguenard laboratory.

Eric I. Knudsen, Ph.D. Professor of Neurobiology: Research in the Knudsen laboratory explores neural mechanisms of learning and attention. These mechanisms are studied in the brain pathways that underlie gaze-control in barn owls. The instructive effects of experience on biochemical, anatomical and functional mechanisms are studied at the levels of single cells, circuits and behavior. In addition, mechanisms that regulate excitability in these pathways are studied in the context of attention, and the influences of these attentional mechanisms on mechanisms of learning are investigated. Techniques employed in the laboratory include in vivo neurophysiology, pharmacology, microstimulation, anatomical pathway tracing, and behavioral conditioning.

Liqun Luo, Ph.D. Associate Professor of Biological Sciences (New Training Faculty). Dr. Luo’s uses molecular genetic approaches to address questions of neural circuit formation. He has recently developed a modern genetic analog of Golgi staining, MARCM (for Mosaic Analysis with a Repressible Cell Marker), that has allowed his lab to label small groups or isolated single neurons in the Drosophila brain. With MARCM they can also genetically manipulate only these labeled neurons, for example by deleting a gene of interest to assess its function in the assembly of neural circuits. MARCM has been used to study the morphological development of individual neurons and the formation of specific connections between neurons. His laboratory is currently developing an approach for MARCM in mice, which may allow for fundamental insights into the maladaptive disorganization of mammalian brain circuits during epileptogenesis.

Susan McConnell, Ph.D., Susan B. Ford Professor of Biological Sciences: Dr. McConnell's interests in developmental neurobiology involve studies of neurogenesis and neuronal migration in the developing cerebral cortex, the specification of discrete neuronal phenotypes through cell lineage and cell-cell interactions, the control of axonal growth between developing neocortex and targets, and factors that influence the formation of lamina-specific axonal connections within the neocortex. Trainees in her laboratory learn a variety of investigative approaches including transplantation of neuronal precursor cells, time-lapse imaging using laser scanning confocal microscopy, molecular biological aspects of cell-target identification and migration, cell and tissue culture, in situ hybridization, and intracellular electrophysiology and dye fills in brain slices together with axonal tracing techniques, and genetic manipulations of mouse development. Dr. McConnell has found that multipotent neuronal precursors in the embryonic cerebral cortex make an early commitment to generating young neurons that are destined for specific cortical layers just prior to the precursor cell's final mitotic division.

Daniel Madison, Ph.D., Associate Professor of Molecular and Cellular Physiology: Dr. Madison has used a variety of electrophysiological techniques to study the mechanisms of synaptic transmission and plasticity in the mammalian hippocampus. A main focus in the lab is the study of activity induced synaptic plasticity, namely long-term potentiation (LTP) and long-term depression (LTD). LTP is a persistent increase in synaptic strength that occurs after a brief period of high frequency activity in a synaptic connection, while LTD is the weakening of synaptic strength that occurs following a prolonged period of low frequency synaptic activation. LTP and LTD are the most widely studied and compelling models for mechanisms underlying memory formation in the mammalian central nervous system. Most recently, Dr. Madison has been involved in studies of LTP and LTD at synapses between single pairs of synaptically coupled hippocampal neurons. These include experiments probing the function of both the presynaptic terminal and postsynaptic spine during LTP and LTD. These experiments have led to the understanding that synapses can exist in a number of distinct synaptic states. The plastic state in which a synapse resides dictates and limits the potential for that synapse to undergo further plasticity. As such, this demonstrates that synapses are sensitive to their recent history with regard to thier ability to undergo synaptic plastic changes.

Robert Malenka, M.D., PhD., Professor of Psychiatry and Behavioral Sciences: Dr. Malenka's primary interest is in the detailed mechanisms by which activity, neurotransmitters and drugs modify synaptic transmission in a variety of brain regions including the hippocampus, somatosensory cortex, nucleus accumbens and ventral tegmental area. A major goal of his laboratory is to elucidate both the specific molecular events that are responsible for the triggering of various forms of synaptic plasticity and the exact modifications in synaptic proteins that are responsible for the observed, long-lasting changes in synaptic efficacy. His work on the mechanisms of long-term potentiation (LTP) and long-term depression (LTD) has led to the novel hypothesis that activity can rapidly and profoundly influence the synaptic distribution of glutamate receptors. Trainees in Dr. Malenka's lab learn a range of cell biological, molecular and electrophysiological techniques that are applied to both brain slices and primary cultured neurons. These techniques include whole cell patch clamp recording, immunocytochemical localization of synaptic proteins, and transfection of cDNAs to express recombinant proteins. Dr. Malenka currently holds the Pritzker Chair of Psychiatry and has received a number of awards for his research including the Young Investigator Award from the Society for Neuroscience and several career development awards from NIH.

William Mobley, M.D., PhD., Professor of Neurology and Neurological Sciences: Dr. Mobley studies the actions of NGF and other trophic factors in the CNS. Building on the lab’s earlier demonstration that NGF is a neurotrophic factor of basal forebrain cholinergic neurons (BFCNs), recent studies have focused on three themes: 1) the trafficking of NGF receptors in vitro and in vivo; 2) the contribution of NGF signaling in BFCNs to synaptic plasticity of cortical and hippocampal afferents; and 3) abnormal NGF signaling and receptor trafficking in a mouse model of Down syndrome (DS) and Alzheimer’s disease (AD). The lab has been pursuing the hypothesis that NGF signaling leads to the creation of “signaling endosomes”, organelles formed by endocytosis in which NGF continues to be bound to its TrkA receptor. The precise composition and source of the signaling endosome is being studied. Dr. Mobley has defined a retrograde NGF signaling defect that results in atrophy and dysfunction of BFCNs in a genetic model of DS and AD, the partial trisomy 16 mouse. Experiments have also recently begun to examine the molecular and cellular events important for synaptic plasticity. The lab’s focus has been on the modulation of glutamatergic synapses by cholinergic inputs to postsynaptic cortical and hippocampal targets. In particular, the work addresses the hypothesis that by modulating cholinergic inputs, NGF has a powerful, albeit indirect, role in regulating synaptic plasticity. If true, these studies will elucidate a novel and important role for NGF that contributes to the biology of excitable neural systems. Trainees in Dr. Mobley’s laboratory learn a variety of techniques including phase and confocal microscopy, immunocytochemistry, immunoprecipitation and blotting, ELISA measurement of NGF and other neurotrophins, RNA isolation, PCR, DNA sequencing, cell culture, cell fractionation, membrane isolation, in situ hybridization, and laser capture methods for RNA and protein measurements.

David Prince, M.D., Professor of Neurology and Neurological Sciences: Dr. Prince is the former director of the Epilepsy Training Program. Current research directions in Dr. Prince's laboratory include 1) developmental studies of neuronal function in normal and epileptogenic rat neocortex, including experiments focused on cellular electrophysiology and anatomy of cortical developmental malformations; 2) anatomic and physiologic properties of neurons in areas of chronic cortical injury and epileptogenesis in a model of post-traumatic epilepsy studied in vitro; alterations of membrane properties and reorganization of receptors and cortical circuits occurring after such injuries are being investigated; 3) actions of transmitters and neuropeptides within intra-thalamic circuits as they relate to rhythmic activities in models of petit mal epilepsy; and 4) electrophysiology and anatomy of cortical interneurons, and their modulation by neurotransmitters. Trainees in his laboratory learn a variety of techniques including use of in vitro neocortical, hippocampal, and thalamic slices; combined physiologic-anatomic analysis of labeled neurons; immunocytochemistry; methods for drug application and assessment of physiological effects of agonists; models of acute epileptogenesis; and production of chronic epileptogenic foci in mammalian brain in vivo. Dr. Prince and his colleagues and fellows have employed patch-clamp techniques to study whole-cell currents and single channel activities from cortical and thalamic neurons in slices, using both “blind” slice-patch methods and infrared video microscopy to record from directly-visualized cells. Collaborative interactions have been maintained with Dr. Huguenard and more recently with Drs. Reimer, McConnell, and Mobley. As of 5/1/04, there are five postdoctoral fellows in Dr. Prince’s laboratory.

Richard Reimer, MD, Assistant Professor of Neurology and Neurological Sciences (New training faculty): Dr. Reimer recently joined the Stanford faculty after finishing a residency in neurology at UCSF and post-doctoral fellowship with Dr. Robert Edwards at UCSF. His post-doctoral work focused on identifying transporter proteins involved in neurotransmitter release and metabolism. His laboratory used molecular, biochemical and cell biological approaches to understanding how transporters are involved in the normal physiology of neurons and how their activity is modulated in pathological states including animal models of epilepsy. Trainees in his laboratory will learn techniques for studying expression and function of transporters, metabolism of neurotransmitters and trafficking of proteins.

Robert Sapolsky, Ph.D. Professor of Biological Sciences, Neurology and Neurological Sciences: Dr. Sapolsky's interests are in the cellular and molecular mechanisms underlying necrotic neuronal death, the role of stress and of glucocorticoids in promoting this process, and the use of gene therapy approaches using viral vectors to protect neurons from injury. His trainees gain experience in primary neuronal culturing, use of in vitro and in vivo models of damage to neurons, microdialysis studies of excitatory amino acid trafficking, measurements of calcium concentrations in cytoplasm, detection of reactive oxygen species and quantification of oxidative damage, and molecular biological techniques for construction and delivery of viral vectors. The Sapolsky laboratory was among the first to document that sustained stress can damage the hippocampus and that glucocorticoids are critical to such neurotoxicity. These agents also impair the capacity of hippocampal neurons to survive after insults including seizures. Cellular and molecular events leading to hippocampal neuronal death are being examined, and in addition, approaches are being designed to confer resistance to such events through overexpression of potentially protective genes. Dr. Sapolsky's contributions have been recognized by receipt of several awards including the Lindsley Prize and a Young Investigator of the Year Award from the Society for Neuroscience.

Examples of general areas of research training available:

Developmental studies: Fellows interested in cortical development might get their primary laboratory experience with Dr. McConnell learning techniques of developmental neurobiology applied to studies of neurogenesis and neuronal migration in the developing cerebral cortex, or with Dr. Barres, working on glial influences on neuronal development and synapse formation. Investigative approaches would include those of molecular biology, in situ hybridization, tissue culture and transplantation as well as electrophysiological and anatomic methods in use in these laboratories. Such a trainee might spend time in Dr. Prince's laboratory learning methods for producing and studying epileptogenic cortical malformations, and applying neuroanatomic and slice-patch electrophysiological techniques to examine disorders of development in such models. Suggested courses: Comparative Medicine 207, (Comparative Neuroanatomy, Buckmaster); Biology 258 (Neural Development, McConnell).

Use-dependent changes in excitability: Another general area of trainee research might be long-term changes in neuronal and synaptic properties associated with use of circuits (e.g. the long-term potentiation or kindling models). Such experiments could be pursued in hippocampal slices in Dr. Madison's laboratory using current clamp and patch-clamp techniques. Trainees in Dr. Malenka’s laboratory would study cellular and circuit synaptic physiology and its modulation by activity, neurotransmitters and intracellular signaling, and would have opportunities to apply these techniques to models of neurological disease. Suggested courses: Neurobiology 254 (Molecular and Cellular Neurobiology, Luo & Stryer); Neurobiology 216 (Genetic Analysis of Behavior, Clandinin & Goodman).

Cellular neurophysiology-neuropharmacology: In the laboratories of Drs. Buckmaster, Fisher, Huguenard, Madison, Malenka or Prince, a trainee whose interests focus on cellular neurophysiology might initially learn to apply the techniques of sharp and whole cell recordings to neurons of slices using either the "blind" slice-patch approach, or infra-red video microscopy to visualize neurons. Methods for analysis of spontaneous and evoked whole cell synaptic currents, and effects of drugs and neurotransmitters on these might be employed. Experiments might focus on areas such as regulation of normal cell and circuit excitability; electrophysiology, structure and pharmacology of interneurons and pyramidal cells; and biophysical properties of voltage-and agonist-activated currents or single channel properties in subclasses of neurons. Experience would also be gained in methods for intracellularly labeling, reconstructing and analyzing recorded neurons. A collaborative project with Dr. Luo’s or Dr. Reimer’s laboratory would acquaint the trainee with methods for assessment of genetic regulation of circuits, or neurotransmitter recycling, as appropriate to his/her primary project. Suggested courses: Molecular and Cellular Physiology 215 (Synaptic Transmission, Smith, Madison); Molecular and Cellular Physiology 256 (Molecular Physiology of Cells, Aldrich & Maduke), Neurology 220 (Computational Neuroscience, Huguenard & Sanger).

Molecular neurobiology: Molecular neurobiological techniques are being employed in the laboratories of Drs. Barres, Huguenard,Luo, Madison, Malenka, McConnell, Reimer and Sapolsky, to examine aspects of cortical development, mechanisms of neurosecretion, second messengers, and regulation of gene expression and factors in hippocampal cell death, as described in Section B-2 above. A trainee involved in such experiments might learn to use a range of methods including in situ hybridization, site directed mutagenesis, gene transfer using viral vectors, cloning techniques, polymerase chain reaction applied to single neurons, Southern blots, etc. Depending upon the nature of the problem under investigation, it might be possible for the trainee to learn to apply other complementary techniques. For example, a combined molecular-electrophysiological approach could be used to investigate the molecular basis for functional differences in agonist-activated synaptic currents in different cell types, or in a given type of neuron in control versus injured or epileptogenic cortex, using single cell PCR together with patch clamp methods. Suggested courses: Neurobiology 254 (Molecular and Cellular Neurobiology, Luo & Stryer); Neurobiology 216 (Genetic Analysis of Behavior, Clandinin & Goodman); Molecular and Cellular Physiology 256 (Molecular Physiology of Cells, Aldrich & Maduke)

Experimental epileptology: Mechanisms underlying abnormal activities during chronic epileptogenesis might be studied in models of post-traumatic epilepsy or cortical malformations in Dr. Prince’s laboratory, using combinations of anatomical, electrophysiological and pharmacological techniques applied to epileptogenic slices. The fellow might elect to work in Dr. Fisher’s or Dr. Buckmaster’s laboratory and examine models of temporal lobe or acquired absence epilepsy by combining both in vivo and in vitro cellular recording and labeling techniques and immunocytochemical approaches. A project in Dr. Sapolsky’s laboratory might involve acquisition of techniques for gene therapy of epileptogenic lesions in hippocampus or neocortex, and studies of approaches to neuroprotection in epilepsy. Trainees might elect to study models of abnormal intrathalamic rhythms and their modulation by neurotransmitters and peptides, or callosally mediated excitation in epileptogenic neocortical lesions in Dr. Huguenard’s laboratory. Joint training in cortical development or molecular mechanisms of synaptic processes in epileptogenesis might be obtained in collaboration with Drs. Barres, McConnell, Luo, Reimer or Malenka, as appropriate. Trainees interested in the role of trophic factors in post-injury epileptogenesis might design projects in collaboration with Dr. Mobley’s laboratory. Suggested courses: Neurology 205 (Clinical Neuroscience, Reimer, Mobley, Yang, Huguenard); Psychology 206 (Behavioral Neuroscience, Wandell, Wine); Molecular and Cellular Physiology 215 (Synaptic Transmission, Smith, Schwartz, Madison).

Training in clinical epileptology: Occasionally, a postdoctoral fellow who has completed a residency in clinical neurology may want to gain experience in clinical epileptology, as well as obtain basic research training. This program does not support training in clinical epileptology per se, however there is opportunity for such M.D. trainees to maintain their exposure to clinical medicine by spending ½ day/week in some clinically related area (see Section B-3d above). It is thus possible for such individuals to attend an epilepsy clinic and read EEGs with one of the attendings on a regularly scheduled basis, and become more familiar with clinical epilepsy in this way. For those who want more substantial clinical exposure, with the assistance of the head of the clinical epilepsy program, it has been possible to arrange a block rotation in clinical epilepsy, supported by Stanford Hospital, once they have completed substantial research training. Our bias is that a career combining significant basic laboratory research in epilepsy-related areas with clinical epileptology may be unrealistically demanding, however, whatever the individual’s final career direction, exposure to both areas does provide significant benefits.

Courses, seminars and conferences: Postdoctoral fellows will have the opportunity to supplement their laboratory training with a wide variety of graduate courses in the major areas of the neurosciences. Those fellows who have not had extensive background in neuroscience will be encouraged by their sponsor to take at least one course per year in areas relevant to their research training program. These include lecture courses, seminars, and classes in specialized laboratory techniques. Examples are provided above in Section B-3e, with the summary of general areas of research training. Appendix B lists selected courses for predoctoral students in the neurosciences which might be audited by postdoctoral fellows. All fellows are required to attend a course on Responsible Conduct of Research (Med 255) described in Section D below and are also encouraged to attend Neurobiology 300, a course on Professional Development and Ethics.

Seminar series: The fellows of the training program will attend an Epilepsy Seminar Series. A speaker from the Stanford neuroscience community or another institution is invited to give a seminar once a quarter and spend time informally discussing ongoing research and new experimental approaches to problems of epilepsy-related research with trainees. In addition, fellows and faculty attend the Frontiers in Neuroscience, Fundamental Themes in Neuroscience, and Neurobiology of Disease series, each of which runs for one quarter; neuroscience seminars of interest sponsored by the Neuroscience Ph.D. Program and Department of Neurology and Neurological Sciences; as well as selected others arranged by Neurobiology, Biology, Molecular and Cellular Physiology, and Pharmacology. Appendix A contains a partial list of recent research seminars.

Epilepsy Program Conference: Dr. Prince has organized an Epilepsy Conference, held 2 to 4 times per year, which is attended by fellows supported by the Epilepsy Training Program, neurology residents and others, together with Program faculty. The purpose is to give trainees an opportunity to interact and review selected problems in epilepsy from both clinical and basic perspectives. Typically one clinical and one basic research fellow review a selected subject. Topics that have been covered are listed in Appendix C.

Clinical Epilepsy Conferences: Trainees with interests in clinical epileptology may occasionally attend other conferences including a weekly epilepsy EEG conference at which video EEG records of hospitalized patients in the Epilepsy Unit are reviewed, and a case conference. All trainees are encouraged to familiarize themselves with the phenomenology of human epilepsy. During their fellowship, trainees visit the inpatient Epilepsy Monitor Unit where one of the clinical epileptologists discusses with them the techniques used to diagnose and classify epilepsy and reviews tapes of various types of epilepsy.

Postdoctoral trainees: Qualifications, criteria, procedures: Research training is provided in areas relevant to basic science aspects of epilepsy for 1) candidates with M.D., M.D./Ph.D. or other medical degrees, and 2) individuals who have Ph.D degrees. From past experience, most M.D. or M.D./Ph.D. candidates interested in epilepsy research training will have completed a residency in clinical neurology, however, well-qualified candidates from other clinical neuroscience backgrounds (Neurosurgery, Psychiatry), or those who have chosen not to enter postdoctoral medical specialty training, will be considered. Candidates must have interests in developing academic careers that will be relevant to epilepsy-related research and must be U.S. citizens or permanent residents to be eligible for support. Candidates will be selected by a committee consisting of several members of the faculty of the Epilepsy Training Program, appointed by the program director. Evaluation will be based upon 1) past academic record including grade point average, GRE or MCAT scores; 2) letters of evaluation from predoctoral sponsor, head of the residency program, Department chairperson, etc. as appropriate; 4) previous research experience; 5) career goals and interests in epilepsy and 6) impressions of faculty following an interview. Although the committee will take into account previous research experience among M.D. applicants, it will endeavor also to identify those who, in the absence of such experience, have significant potential to become effective investigators and faculty members, on the basis of their academic and clinical records and career goals. The committee will make appropriate matches between the interests of a given applicant and the research activities of particular faculty members. Participation in research involving more than one neuroscience discipline, and collaborative research between laboratories will be encouraged.

Examples of recent publications involving trainees:

Bandrowski, A.E., Huguenard J.R. and Prince, D.A. (2003) Baseline glutamate levels affect group 1 and II mGluRs in layer V pyramidal neurons of rat sensorimotor cortex. J. Neurophysiol. 89(3):1308-16.

Barth, A.L. (2002) Differential plasticity in neocortical networks. Physiol. Behav. 77(4-5):545-50. Review.

Barth, A.L. and R.C. Malenka. (2001) NMDAR EPSC kinetics do not regulate the critical period for LTP at thalamocortical synapses. Nat. Neurosci. 4(3):235-6.

Basu, SB and Mobley WC (2004) Decreased mossy cell population and innervation in dentate gyrus of Ts65Dn mice, a model for Down Syndrome. (not in PubMed) waiting for confirmation from Mobley lab)

Browne SH, Kang J, Akk G, Chiang LW, Schulman H, Huguenard JR, Prince DA. (2001) Kinetic and pharmacological properties of GABA(A) receptors in single thalamic neurons and GABA(A) subunit expression. J Neurophysiol. Nov;86(5):2312-22.

Chan, R. S., E. D. Huey, H. L. Maecker, K. M. Cortopassi, S. A. Howard, A. M. Iyer, L. J. McIntosh, O. A. Ajilore, S. M. Brooke, and R. M. Sapolsky. (1996) Endocrine modulators of necrotic neuron death. Brain Pathol. 6:481 491.

Chiang LW, Grenier JM, Ettwiller L, Jenkins LP, Ficenec D, Martin J, Jin F, DiStefano PS, Wood A. (2001) An orchestrated gene expression component of neuronal programmed cell death revealed by cDNA array analysis. Proc Natl Acad Sci U S A. Feb 27;98(5):2814-9.

Christopherson K, Ullian EM, and BA Barres (2004) Thrombospondin is an astrocyte-secreted protein sufficient to induce synaptogenesis. SCIENCE, submitted. (Co-first authors)

Dumas, T.C. & Sapolsky, R.M. (2001) Gene therapy against neurological insults: sparing neurons versus sparing function. Trends in Neuroscience, 24(12):695-700.

Dumas, T.C., McLaughlin, J.R., Ho, D.Y., Lawrence, M.S. & Sapolsky, R.M. (2000) Gene therapies that enhance hippocampal neuron survival after an excitotoxic insult are not equivalent in their ability to maintain synaptic transmission. Experimental Neurology, 166:180-189.

Dumas, T.C., McLaughlin, J.R., Ho, D.Y., Meier, T.J. & Sapolsky, R.M. (1999) Delivery of herpes simplex virus amplicon-based vectors to the dentate gyrus does not alter hippocampal synaptic transmission in vivo. Gene Therapy, 6(10):1679-1684.

Foster, T.C. & Dumas, T.C. (2001) Mechanisms for increased hippocampal CA3-CA1 synaptic strength following differential experience. Journal of Neurophysiology, 85(4):1377-1383.

Graber, K., and Prince, D.A. (1999) Tetrodotoxin prevents post-traumatic epileptogenesis in rats, Annals of Neurol., 46:234-242.

Graber, K.D., and Prince, D.A. (2004) A critical period for prevention of neocortical post-traumatic epileptogenesis in rat. Annals of Neurology, in press.

Halabisky, B., Shen, F., Huguenard, J.R., and Prince, D.A. (2006).Electrophysiological classification of somatostatin-positive interneurons in mouse sensorimotor cortex, J. Neurophysiol. 96: 834-¬845,

Huntsman, M.M. and Huguenard, J.R. (2006) Fast IPSCs in rat thalamic reticular nucleus require the GABAA receptor b1 subunit. J. Physiol. 572:459-475.

Huntsman, M.M., and Huguenard, J.R. (2000) Nucleus-specific differences in GABAA-receptor-mediated inhibition are enhanced during thalamic development. J. Neurophysiol. 83:350-35857.

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.

Jacobs, K. M., B. J. Hwang, and D. A. Prince. (1999) Focal epileptogenesis in a rat model of polymicrogyria. J. Neurophysiol. 81:159 173.

Jacobs, K. M., M. Mogensen, E. Warren, and D. A. Prince. (1999) Experimental microgyri disrupt the barrel field pattern in rat somatosensory cortex. Cereb. Cortex. 9:733-744.

Jacobs, K.M., Graber, K.D., Kharazia, V.N., Parada, I., and Prince, D.A. (2000) Postlesional Epilepsy: The Ultimate Brain Plasticity, Epilepsia, 41: Suppl.6: S153-S161.

Jacobs, K.M., Kharazia V.N., Prince, D.A. (1999) Mechanisms underlying epileptogenesis in cortical malformations. Epilepsy Res., 36:165-188.

Jacobs, KM and Prince, D.A. (2005) Excitatory and inhibitory postsynaptic currents in a rat model of epileptogenic microgyria , J. Neurophysiol. 93:687-696.

Kang, J., J. R. Huguenard, and D. A. Prince. (1996) Development of BK channels in neocortical pyramidal neurons. J. Neurophysiol. 76:188 198.

Kang, J., J. R. Huguenard, and D. A. Prince. (1996) Two types of BK channels in immature rat neocortical pyramidal neurons. J. Neurophysiol. 76:4194 4197.

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