Minimally-invasive manipulation of spared and hypoactive interneurons reduces CA1 synchronization and nonspatial behavior alterations in epilepsy models

Temporal lobe epilepsy (TLE) is associated with seizures and severe cognitive impairments, including memory deficits. The dysfunction of a large population of hippocampal interneurons, composed of various subtypes, is proposed as a key mechanism and a therapeutic target. However, the nature and extent of alterations in hippocampal inhibitory neurons remain unclear, as does their impact on TLE pathology. To address this issue, we combined immunolabeling, calcium imaging, electrophysiology, chemogenetic tools, and behavioral assays in mouse pilocarpine TLE models to investigate the survival and changes in the activity of a large population of Dlx-expressing interneurons and test the effect of their manipulation on seizures and cognitive impairments. We observed that a large population of Dlx-expressing interneurons, which includes Cholecystokinin-, Parvalbumin-, and Somatostatin-positive cells, was overall spared from histological damage occurring in CA1 from TLE mice, despite subtype-specific vulnerability. In addition, Dlx-expressing interneurons exhibited reduced activity in vitro, correlated to hypersynchrony in the CA1 network. Enhancing CA1 interneuron discharge in vitro using a chemogenetic strategy rescued CA1 activity and synchronization. In vivo, a minimally invasive approach to normalize interneuron activity does not rescue the full range of pathological features associated with TLE, but significantly reduces some cognitive impairments, particularly behaviors related to nonspatial learning and memory. Our findings suggest that enhancing local CA1 interneuron activity can restore local network balance and improve cognitive function in TLE.