Minimally invasive activation of spared interneurons alleviates local CA1 hypersynchrony and behavioral deficits in a model of temporal lobe epilepsy

Abstract

BackgroundTemporal lobe epilepsy (TLE) is associated with severe cognitive impairments including memory deficits. The dysfunction of hippocampal inhibitory neurons is proposed as a key mechanism and possible target for therapeutic approaches. However, the nature and extent of alterations in hippocampal inhibitory neurons remain unclear, as does their impact on behavioral impairments associated with TLE.MethodsWe investigated the role of inhibitory neurons from the CA1 hippocampal region on memory deficits associated with TLE, considering both the survival and changes in the activity of a large population of interneurons. To this end, we used a combination of immunolabelling, calcium imaging, electrophysiology, human-applicable chemogenetic tools, and behavioral testing on a reliable mouse pilocarpine TLE model.ResultsWe show that in TLE mice with severely disturbed spatial behavior, CA1 major interneuron populations are spared from histological damages that affect the epileptic hippocampus (e.g., sclerosis). However, CA1 interneurons fire less in epileptic than in control conditions, resulting in increased synchronization and activity of the epileptic CA1 network in vitro. Restoring CA1 interneuron discharge using a chemogenetic strategy rescued CA1 activity and synchronization in vitro. In vivo, the minimally invasive chemogenetic activation of hippocampal interneurons does not affect generalized seizures but reduces behavioral alterations.ConclusionsOur data suggest that rescuing CA1 local network dynamics using interneurons as a lever could be sufficient to decrease behavioral deficits related to TLE.