INTERNEURON TRANSPLANTS AS A TREATMENT FOR SEIZURES AND SOCIAL DEFICITS IN A MOUSE MODEL OF DRAVET SYNDROME

GABAergic inhibitory interneuron transplants have been shown to ameliorate seizures and epilepsy-associated behavioral deficits in several preclinical rodent models of epilepsy. These studies have generally focused on focal temporal epilepsy models, but less is understood about the efficacy of targeted interneuron transplants in epilepsy models caused by selective interneuron dysfunction, such as Dravet syndrome. Dravet syndrome (DS) is a treatment-resistant pediatric epilepsy caused by loss of function variants in SCN1A, which codes for the voltage-gated sodium channel  subunit Nav1.1. DS is also characterized by high rates of autism spectrum disorder and intellectual disability. In this dissertation, we first review the role of interneuron dysfunction in DS, and we review the promising history of interneuron transplants as a potential treatment for epilepsy. Next, we show that the classic ‘interneuron hypothesis’ of DS may be incomplete, as intrinsic firing deficits of interneurons were shown to be transient in Scn1a+/- mice, even though hyperexcitability persists in excitatory corticohippocampal circuits. Then, we explore hippocampal interneuron transplants into either neonate or adult Scn1a+/- mice as a potential treatment for spontaneous seizures, temperature-induced seizures, and social deficits. We find that transplants performed in adult Scn1a+/- mice result in high-density bilateral hippocampal-targeted grafts that show a statistically insignificant trend of decreasing spontaneous seizure frequency, without influencing temperature-induced seizure thresholds or social deficits. We also show that transplants into neonate Scn1a+/- mice did not have an apparent effect on seizures or social behavior, although methodological and technical constraints rendered this finding inconclusive. We conclude by discussing the potential of future interneuron transplants, involving specific interneuron subclasses and brain regions, to improve our understanding of circuit abnormalities that underlie neurodevelopmental disorders such as Dravet Syndrome.