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Neuroscience Graduate Program at UCSF
Cellular Mechanisms of Epileptogenesis
Epilepsy is one of the most common neurological disorders, affecting nearly 2.5 million Americans - many of them children. Because the hallmark feature of an epileptic brain is the occurrence of abnormal electrical discharge (seizure), our laboratory is focused on the intrinsic, synaptic and non-synaptic mechanisms that regulate neuronal excitability. By studying animal models of epilepsy and tissue obtained from patients undergoing surgery for intractable epilepsy we hope to obtain a better understanding of the cellular events underlying epileptogenesis. Techniques include the use of in vitro brain slices for electrophysiological recording of membrane properties and synaptic function (using visualized patch-clamp methods); molecular analysis of gene expression using in situ hybridization; immunohistochemical and morphological studies of neuronal structure and protein expression; pharmacological analysis of seizure modulation in knockout mice; and a forward-genetic screening strategy to uncover novel seizure-related gene mutations.
Epilepsy Associated with a Malformed Brain
A major focus of our research is on the development (and analysis) of animal models for specific childhood seizure disorders. Epileptic seizure disorders observed in children are often medically intractable and associated with some type of brain malformation. Our research is specifically designed to study rodents with malformations resembling those primarily seen in children. For example, a heterozygotic Lissencephaly-1 mouse mimics the haploinsufficiency associated with this pediatric epilepsy condition. The hippocampus in these mice shows clear signs of malformation including a severe loss of lamination and granule cell dispersion. We are currently studying the excitatory and inhibitory circuits in this malformed hippocampus, using visualized patch-clamp recording techniques. Additional anatomical studies are aimed at understanding how newly born neurons contribute to granule cell dispersion.
Seizures and Seizures Resistance in Zebrafish
Genetic screening approaches wherein mutagen treatment introduces random mutations into the genome and resultant mutants are recovered in subsequent generations is a powerful and un-biased method to identify epilepsy genes. These studies take advantage of a genetically tractable vertebrate e.g., zebrafish larvae (Danio rerio). To demonstrate the relevance of zebrafish studies to higher vertebrates we initially performed (i) behavioral studies to analyze seizure activity in fish exposed to a common convulsant agent, (ii) electrophysiological studies to monitor interictal and ictal forms of induced epileptiform-like activity and (iii) pharmacology studies to compare anticonvulsant drug efficacy between fish and mice. Six “seizure resistant” zebrafish mutants were recently isolated in a genome-wide forward-genetic mutagenesis screen. Characterization and genetic mapping of these mutants is currently underway and we recently began to incorporate morpholino antisense strategies to further study the neurobiology of epilepsy in zebrafish.
Interneurons and Neural Progenitor Cells
GABAergic interneurons provide the primary source of inhibition in the central nervous system. Using human tissue derived from patients with intractable epilepsy (i.e., focal cortical dysplasia) and animal models lacking Dlx transcription factors necessary for the migration and differentiation of cortical interneurons (e.g., Dlx1 null mice), we have identified conditions where reduced interneuron density and loss of inhibition directly contributes to an epileptic phenotype. At the same time, working in close collaboration with Drs. John Rubenstein and Arturo Alvarez-Buylla, we have shown that embryonic neural progenitor cells from the medial ganglionic eminence (MGE) can be used to generate new and functional interneurons when grafted into a host brain. We are currently exploring whether MGE progenitor cells exhibit "antiepileptic" potential following transplantation in a variety of rodent epilepsy models.
Joy Sebe
Postdoctoral Fellow
University of Washington
Gabriela Hortopan
Postdoctoral Fellow
University of Turin
Sally Chege
Graduate Student
Washington State University
Matthew Dinday
SRA
UC Berkeley
Suneel Agerwala
SRA
Pace University
Elizabeth Looke-Stewart
SRA
Princeton University
Link to Publications via PubMed
Cobos I, Calcagnotto ME, Vilaythong AJ, Thwin MT, Noebels JL, Baraban SC, Rubenstein JL (2005) Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nature Neuroscience 8, 1059-1068.
Calcagnotto ME, Paredes MF, Tihan T, Barbaro NM, Baraban SC (2005) Dysfunction of synaptic inhibition in epilepsy associated with focal cortical dysplasia. Journal of Neuroscience 25, 9649-9657.
Alvarez-Dolado M, Calcagnotto ME, Karkar KM, Southwell DG, Jones-Davis DM, Estrada RC, Rubenstein JL, Alvarez-Buylla A, Baraban SC (2006) Cortical inhibition modified by embryonic neural precursors grafted into the postnatal brain. Journal of Neuroscience 26, 7380-7389.
Wang Y, Greenwood JS, Calcagnotto ME, Kirsch HE, Barbaro NM, Baraban SC (2007) Neocortical hyperexcitability in a human case of tuberous sclerosis complex and mice lacking neuronal expression of TSC1. Annals of Neurology 61, 139-152.
Scott Baraban, Ph.D.
Phone
415-476-9473
Physical Address
U-240, Clinical Sciences Building, Parnassus
Mailing Address
UCSF
Department of Neurological Surgery
513 Parnassus
Box 0520
San Francisco, CA 94143-0520
For internal campus mail
Box 0520
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