Scott Baraban, PhD
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. We recently showed that zebrafish can be used in a high-throughput screening strategy to identify lead compounds for intractable forms of pediatric epilepsy.
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 mouse models of epilepsy. Further development of this cell-based interneuron strategy is currently underway.