Project Summary/Abstract Cell transplantation, using GABAergic interneurons that integrate in host brain circuits, and function similar to endogenous inhibitory neurons could offer a novel therapeutic alternative for intractable epilepsies. Our work, over the past two decades, demonstrated that GABAergic progenitor cells derived from murine embryonic medial ganglionic eminence (MGE) integrate into host circuits (following transplantation in neonatal or adult mice), where they make functional inhibitory synapses, efficiently suppress epileptic seizure activity, and correct behavioral comorbidities associated with epilepsy. To establish an alternative source of MGE progenitor cells that would facilitate translation of this disease-modifying transplantation strategy to larger species, we recently established protocols using porcine embryonic MGE progenitor cells. Building on these findings, two specific aims are proposed: (i) to optimize intra-hippocampal xenotransplantation of porcine embryonic MGE progenitor cells and (ii) to evaluate the range of therapeutic benefits possible with porcine embryonic MGE progenitor cells. Techniques will involve cutting-edge electrophysiology, optogenetic and calcium imaging methods (in vitro and in vivo) to study functional integration of MGE-derived interneurons. Video-EEG monitoring, rodent epilepsy models, sophisticated behavioral assays, and confocal microscopy techniques will also be applied. Our results promise to provide new information about porcine MGE progenitors and direct demonstration(s) of the potential for xenotransplantation as a treatment for intractable epilepsies.