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Neuroscience Graduate Program at UCSF
Neurobiology of Epilepsy
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 primarily focused on the intrinsic, synaptic and molecular mechanisms that regulate neuronal excitability. By focusing on animal models of epilepsy (in mice and zebrafish) and tissue obtained from patients undergoing surgery for intractable epilepsy, we hope to obtain a better understanding of the cellular events underlying epileptic activity. Using cell grafting strategies, based on the generation of new inhibitory interneurons in the host brain, we are also hoping to develop new treatments for patients with intractable epilepsy. 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, qPCR and micro-array; immunohistochemical and morphological studies of neuronal structure and protein expression; pharmacological analysis including high-throughput drug screening of seizure modulation in knockout mice; and progenitor-based cell therapies focused on GABAergic interneurons.
Epilepsy Associated with a Malformed Brain
A historical 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 (generated in the Wynshaw-Boris laboratory) 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. In these mice, we have uncovered interesting deficits in the trafficking of excitatory synaptic vesicles and aberrant neurogenesis of newborn cells within a dysplastic granule cell layer. We are currently studying the functional consequences of these deficits in heterozygote and conditional Lis1 mutant mice, using visualized patch-clamp recording techniques and pharmacology.
Seizures and Epilepsy in Immature Zebrafish
Pediatric epilepsies are associated with developmental or cognitive co-morbidities and are only poorly controlled by available antiepileptic drugs (AEDs). Unfortunately, existing AED drug discovery programs are not designed to address this problem, as they are primarily based on acute or acquired seizures in adult rodents. Where our work seeks to shift current research in the epilepsy field is two-fold. First, by utilizing immature zebrafish models designed to mimic known single-gene mutations seen in children we are working to establish and characterize the first epileptic zebrafish. These studies focus on gene mutations for Angelman syndrome (ubiquitin E3 ligase), Dravet syndrome (Nav1.1), Benign Neonatal Familial Convulsions (KCNQ) and Lissencephaly (Lis-1). In vivo electrophysiological and behavioral assays developed in our laboratory are used to study epileptic phenotypes in these zebrafish; confocal imaging, in situ hybridization, micro-array and qPCR are also used. Second, by focusing on zebrafish epilepsy mutants we are working to establish a new template for high-throughput cost-effective drug screening with distinct advantages over current rodent-based approaches.
GABA Progenitor Cell Therapy for Epilepsy
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 recently showed that these MGE progenitor cells effectively eliminate spontaneous electrographic seizure activity following transplantation into a mouse model of epilepsy. Further development of this cell-based interneuron strategy is currently underway.
Joy Sebe, Postdoctoral Fellow
Gabriela Hortopan, Postdoctoral Fellow
Robert Hunt, Postdoctoral Fellow
MacKenzie Howard, Postdoctoral Fellow
Christine Arnold, Associate Specialist
Matthew Dinday, Staff Research Associate
Kelly Girskis, Staff Research Associate
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.
Greenwood JSF, Wang Y, Estrada RC, Ackerman L, Ohara PT, Baraban SC (2009) Seizures, enhanced excitation and increased vesicle number in Lis1 mutant mice. Annals of Neurology 66, 644-653.
Jones DL, Baraban SC (2009) Inhibitory inputs to hippocampal interneurons are reorganized in Lis1 mutant mice. Journal of Neurophysiology 102, 648-658.
Baraban SC, Southwell DG, Estrada RC, Jones DL, Sebe JY, Verdugo-Garcia JMG, Rubenstein JLR, Alvarez-Buylla A (2009) Reduction of seizures by transplantation of cortical GABAergic precursors into Kv1.1 mutant mice. Proceedings of the National Academy of Sciences USA 106, 15472-15477.
Hortopan GA, Dinday MT, Baraban SC (2010) Spontaneous seizures and altered gene expression in GABA signaling pathways in a mind bomb mutant zebrafish. Journal of Neuroscience 30, 13718-13728.
Hortopan GA, Baraban SC (2011) Aberrant expression of genes necessary for neuronal development and notch signaling in an epileptic mind bomb zebrafish. Developmental Dynamics 240(8):1964-76.
Scott Baraban, Ph.D.
Phone
415-476-9473
Physical Address
Health Sciences West (HSW 771)
513 Parnassus Ave.
Mailing Address
UCSF
Department of Neurological Surgery
521 Parnassus
Box 0112
San Francisco, CA 94143-0520
For internal campus mail
Box 0112
Other Websites
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research