Grafted hPSC-derived GABA-ergic interneurons regulate seizures and specific cognitive function in temporal lobe epilepsy

Abstract

Abstract Interneuron loss/dysfunction contributes to spontaneous recurrent seizures (SRS) in chronic temporal lobe epilepsy (TLE), and interneuron grafting into the epileptic hippocampus reduces SRS and improves cognitive function. This study investigated whether graft-derived gamma-aminobutyric acid positive (GABA-ergic) interneurons directly regulate SRS and cognitive function in a rat model of chronic TLE. Human pluripotent stem cell-derived medial ganglionic eminence-like GABA-ergic progenitors, engineered to express hM4D(Gi), a designer receptor exclusively activated by designer drugs (DREADDs) through CRISPR/Cas9 technology, were grafted into hippocampi of chronically epileptic rats to facilitate the subsequent silencing of graft-derived interneurons. Such grafting substantially reduced SRS and improved hippocampus-dependent cognitive function. Remarkably, silencing of graft-derived interneurons with a designer drug increased SRS and induced location memory impairment but did not affect pattern separation function. Deactivation of DREADDs restored both SRS control and object location memory function. Thus, transplanted GABA-ergic interneurons could directly regulate SRS and specific cognitive functions in TLE.