Treating Cortical Epilepsy with Interneuron Transplants

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DESCRIPTION (provided by applicant): Despite advances in the treatment of seizure disorders, medically intractable epilepsy requiring surgical treatment remains a serious problem. The concept of treating seizures by grafting inhibitory interneurons into seizure foci is more than a decade old, but has yet to lead to clinically useful approaches. However, recent studies on the origins and specification of cortical interneurons warrant a new examination of this issue. We propose to use intracerebral grafts of interneuron precursors to treat chronic seizures that are focally induced in the adult mouse cortex. This study combines the expertise of two laboratories at Weill-Cornell Medical College. The PI, an Assistant Professor of Neurological Surgery, studies the propagation of cortical seizures in rodent models of epilepsy using in vivo electrophysiology and intrinsic optical imaging. The co-investigator, an Assistant Professor of Psychiatry, studies the specification of cortical interneuron subtypes in mice using transplantation of interneuron progenitors from the subcortical embryonic forebrain into the postnatal cortex. In Aim 1 the investigators will optimize the protocol for transplantation of interneuron progenitors into Tetanus Toxin (TTx)-induced chronic epileptic foci. In addition, effects of chronic seizures on interneuron migration, survival, and differentiation will be examined. Preliminary data suggest that, like transplants interneuron progenitors into the cortex of normal adult mice, transplants into TTx-induced seizure foci also result in migration, survival, and interneuronal differentiation of substantial numbers cells. Aim 2 will test the system-level functionality of transplanted interneurons by determining their ability to suppress epileptiform activity in the TTx model. Epileptiform activity will be assessed by simultaneous telemetry and video monitoring for several weeks before and several months following transplantation. The capacity to reduce epileptiform discharges with transplants of interneuron progenitor pools that are enriched for distinct interneuron subgroups will be compared to vehicle and cell-based controls. The results will strengthen the rationale for future studies using interneuron-progenitor directed stem cells, and also to explore the use of interneuron progenitors as a cell-based delivery system of anti-epileptic agents. The advances resulting from this proposal should inform efforts to prevent or interrupt intractable epileptogenesis resulting from focal lesions. The application of this research to increasingly clinically-oriented studies will be achieved by consultation with Dr. Theodore Schwartz, a practicing neurosurgeon who is the Director of Research at the Center for Epilepsy Surgery at WMC.