The Baraban Lab is interested in the cellular and molecular basis of epilepsy. Epilepsy is a potentially devastating neurological disorder afflicting nearly 2.5 million Americans. While seizures can be controlled with available medications, a large number of epilepsy patients are medically intractable. Disturbances of cortical development (long recognized as a cause of epilepsy in children) are particularly difficult to treat, little understood, and marked by severe cognitive deficits. How seizures develop and how they can be prevented are of particular interest to our laboratory. Many of our studies exploit rodent models of pediatric epilepsy and tissue surgically resected from patients with intractable forms of epilepsy. Zebrafish, a new addition to the laboratory, have expanded our interests in simple vertebrate epilepsy models. We employ a multi-disciplinary experimental approach incorporating electrophysiology, pharmacology, molecular biology, and genetics.
In thinking about an epilepsy cure, we are also pursuing genetic and progenitor (“stem”) cell strategies. These approaches promise to provide new insights into the genetic basis of seizure suppression and/or offer new strategies for cell repair in an epileptic brain.
Current Research Projects
Epileptogenesis in a Malformed Brain
Cortical malformations are increasingly recognized as a major cause of epilepsy. Although clinical studies suggest that dysplastic neurons (e.g., cells located within a malformation) have epileptogenic properties – and surgical ablation of malformed brain regions is often effective in reducing seizure frequency – little is presently known about how seizures develop in a malformed brain. Our research addresses two fundamental questions in this field: (i) How do dysplastic neurons function and (ii) How do dysplastic cells communicate? To investigate these issues, we primarily use visualized patch-clamp electrophysiological techniques in acute brain slices. Current studies focus on genetically modified mouse models for Type-1 Lissencephaly (Lis1) and Tuberous Sclerosis Complex (TSC), as well as human tissue sections obtained at surgery from patients with focal cortical dysplasia (FCD).
Seizures and Seizure Resistance in Zebrafish
Cellular and genetic factors resulting in seizure susceptibility are now well established. Indeed, nearly epilepsy 200 gene mutations have been identified. However, virtually nothing is known concerning mechanisms of seizure resistance. To address this problem we have undertaken a “reductionist” approach using zebrafish (Danio rerio). Quite remarkably, evoked or spontaneous seizures in zebrafish exhibit behavioral, electrophysiological and pharmacological characteristics that resemble those observed in mammals. Using a large-scale forward-genetic screening strategy we isolated six “seizure-resistant” mutant lines from out of nearly 2000 families. Identification of genes that confer resistance in these mutants is currently underway. At the same time using morpholino antisense techniques, pharmacological manipulations or mutants, we are studying (in zebrafish) the function of a variety of epilepsy genes.
GABA Progenitor Cell Therapy for Epilepsy
Transplantation of neuronal precursors into the CNS offers great promise for the treatment of neurological disease. Recent reports of multipotent neural stem or progenitor cells with the ability to disperse and differentiate into neurons in adult CNS have further raised expectations that defective brain circuits can be repaired. Using transplanted progenitors from the embryonic medial ganglionic eminence (MGE; the primary source of GABAergic inhibitory interneurons) we are exploring the possibility that these cells will influence synaptic function in the host brain and reduce hyperexcitability associated with seizures. By transplanting MGE-derived cells into epileptic mice are directly testing the therapeutic potential of this cell-based approach.