The Stanford Epilepsy Training Program (ETP)
Stanford University School of Medicine and the Neurology Department sponsor a postdoctoral training program in epilepsy research. Epilepsy is a complex disease requiring an integrated multidisciplinary approach designed to effectively train future research leaders in the field. Accordingly faculty with a wide range of relevant expertise in the Departments of Biological Sciences, Molecular and Cellular Physiology, Comparative Medicine, Neurology and Neurological Sciences, Neurobiology, Neurosurgery, and Psychiatry at Stanford University have been assembled to create a training program that attracts fellows to careers in research areas especially relevant to the problems of epilepsy in man. The faculty employ modern neuroscience approaches including live imaging, cellular neurophysiology, optogenetics, biochemistry, genetics, neuroanatomical approaches, and the use of animal model systems for studies of normal and abnormal structure/function. Faculty research interests include cortical neuronal and glial development and function; physiological and morphological changes in nerve cells and circuits in animal models of chronic neocortical and hippocampal epileptogenesis; dissection and intervention of neuronal microcircuits implicated in seizures and epileptogenesis; development, organization, and synaptic physiology of the CNS, especially neocortex, thalamus, hippocampus; cellular and molecular aspects of long-term changes in neuronal excitability; and the roles of gene structure, expression and modulation on neuronal function, especially interneurons. Trainees may learn techniques of whole animal EEG, behavior, and intracranial recording; optogenetics; neurophysiology in reduced preparations such as slices or cultures; anatomic techniques for intracellular labeling and tract tracing, immunocytochemistry and in situ hybridization; cell culture; cell transplantation; experimental gene therapy; and use of transgenic animals. The training program consists of monthly integrative sessions, including seminars, didactic lectures, and clinical content, all focused on epilepsy. Participation of clinical department faculty fosters effective research interactions between trainees and a focus on the interface between basic neuroscience and clinical issues requiring investigation. The positions are advertised nationally and applicants solicited in accord with, and in the spirit of recruiting individuals from diverse backgrounds.
Stanford University School of Medicine has a particular emphasis on collaborative research in Epilepsy, and our training faculty make up the core this effort. A recent NCBI/Pubmed search (Appendix A) with the terms epilepsy and Stanford yielded 88 publications since 2010. Of these 66 were authored in part by ETP faculty and at least 40 of these broadly involved trainees. 12 of the publications were collaborative efforts among ETP faculty, 8 of these with recent appointees to the ETP. These publications appeared in such journals as J Neurosci, PNAS, and Neuron, among others. Note that this is not a comprehensive set of ETP fellow publications. These will be discussed later.
Paul Buckmaster, D.V.M., Ph.D., 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 unit and EEG activity before and during spontaneous seizures, and neurotoxin induced epilepsy in California sea lions. 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, in situ hybridization, immunocytochemistry, confocal microscopy, electron microscopy, and stereological methods.
Robert S. Fisher, MD PhD 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. He has been the main force behind laboratory and recent 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., Professor of Neurology and Neurological Sciences, and Program Director of the ETP.
His early biophysical studies with Doug Coulter of low threshold calcium currents and their modulation by selective petit mal anticonvulsants, and later experiments describing the effects of benzodiazepines and ethosuximide on thalamic neurons and networks, have instigated the development of novel epileptic therapies. Current research directions in Dr. Huguenard’s laboratory include regulation of excitability in thalamic and cortical neurons and the key role of synaptic integration in determining network state. Epilepsy is a network phenomenon and an emergent property of neural networks that stray from their normal function. Synaptic interactions among neurons can vary in a dynamic sense leading to distinct states during the initiation, propagation and termination of seizures. His laboratory studies the transitions between normal network function and these various epileptic states, efforts that have been aided through the use of genetic animal models of spontaneous seizures. He utilizes a number of modern approaches to this end, including live imaging, neurophysiology, and optogenetic circuit dissection and neuromodulation. Mouse knockouts are commonly used to define the roles of specific molecules (ion channels, neurotransmitter receptors, or transporters) 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 chronic EEG studies in animal models of epilepsy, biophysics of voltage-gated and synaptic currents in neurons with in vitro slice preparations, circuit mapping via laser scanning photostimulation (LSPS), multiphoton imaging of neural activity in fine structures (axons, dendrites) via Na+ and Ca2+ imaging, dynamic clamp, real time imaging of neurotransmitter output (esp. glutamate) and computer simulation tools (NEURON, MCell). There are currently 9 fellows in Dr. Huguenard laboratory.
Liqun Luo, Ph.D. Professor of Biology and Investigator of the Howard Hughes Medical Institute. Dr. Luo uses molecular genetics to study the logic of neural circuit organization and assembly. The human brain is made of hundreds of billions of neurons. Most individual neurons have complex dendrites and axons that allow them to receive and send information to thousands of other neurons. Specific neurons participate in specialized neural circuits and perform dedicated functions. To comprehend this bewildering complexity, Dr. Luo’s group uses simpler brains of model organisms to uncover fundamental principles that are likely to be used in our own brain. Dr. Luo’s lab has developed genetic methods in fruit flies and mice that permit labeling and genetic manipulation of individual neurons in intact brains. They use these methods to study how neural circuits are organized in adult and how they are assembled during development. In particular, Dr. Luo’s lab has elucidated mechanisms by which exuberant axons and dendrites are pruned during the wiring of the nervous system. Defects in neuronal process pruning could contribute to epilepsy.
Robert Malenka, M.D., PhD., Nancy Friend Pritzker 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, optogenetics, behavior, 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. His expertise on synaptic plasticity is highly valued by our trainees, as the process of epileptogenesis can be considered as a failure of proper circuit/synaptic homeostatic plasticity.
Brenda Porter M.D., Ph.D, Associate Professor of Neurology and Director of Pediatric Epilepsy at Stanford Children’s Health: Dr. Porter’s current research focuses on 1) The role of transcriptional regulation in the development of epilepsy following an episode of status epilepticus. Using mice and rats the lab is studying how cyclic-AMP response element (CRE) binding proteins promote epileptogenesis and how manipulating CRE transcription can be utilized to prevent epilepsy. 2) Understanding how microRNA expression is regulated following status epilepticus and its implication for the development of epilepsy. 3) The extracellular matrix that surrounds inhibitory interneurons, the perineuronal net has a unique structure that is degraded by proteases following an episode of status epilepticus. The lab is currently focused on how the loss of the net impacts epileptogenesis, the perineuronal net in human epilepsy tissue, and identifying protease inhibitors that will prevent net loss.
Ivan Soltesz, PhD. James Doty Professor and Vice Chair of Neurosurgery, and Professor of Neurology & Neurological Sciences: Dr. Soltesz’s research program is focused on the principles of organization of GABAergic inhibition in the brain and the basis of circuit dysfunction in epilepsy. Current projects in the lab include the selective modulation of different cell types in various parts of the brain to block seizures and ameliorate epilepsy-related cognitive deficits, mechanisms of endocannabinoid control of circuit excitability, the role of interneurons in normal and abnormal network oscillations in the hippocampus, and the development of uniquely realistic, full-scale, 3D models of hippocampal circuits. Trainees in the lab are exposed to a variety of closely integrated experimental and theoretical techniques, including simultaneous patch clamp recordings from identified interneuron-principal cell pairs, rigorous identification of GABAergic interneuronal subtypes, in vivo recordings from different interneurons in awake behaving mice, in vivo imaging techniques, closed-loop in vivo optogenetics, behavioral approaches, and large-scale computational modeling methods using supercomputers.
Thomas Südhof, M.D., Ph.D. Avram Goldstein Professor of Molecular & Cellular Physiology and Investigator of the Howard Hughes Medical Institute: The collective findings of Dr. Südhof’s research program have provided much of our current scientific understanding of behavior of the presynaptic neuron in neurotransmission and synapse formation. His work also has revealed the roles of presynaptic neurons in neuropsychiatric illnesses, such as autism or neurodegenerative disorders. Among the discoveries in his 20 years of research, Südhof revealed how synaptotagmin proteins sense calcium and mediate neurotransmitter release from presynaptic neurons. He also defined the molecules that organize release in space and time at a synapse, such as RIMs and Munc13’s, and identified central components of the presynaptic machinery that mediate the fusion of synaptic vesicles containing neurotransmitters with the presynaptic plasma membrane, the process that ultimately causes neurotransmitter release, and that is controlled by synaptotagmins. Südhof’s lab is currently focused on defining the relationship between specific synaptic proteins and information processing in the brain, with its concordant manifestations in behavior. This large-scale project attempts to provide insight both into the mechanisms underlying synaptic communication, and the processes causing human disease. A focus in the laboratory is synaptic dysfunction in neurodevelopmental disorders such as Autism along with the related cortical hyperexcitability that may be relevant to epilepsy.