Chemogenetic astrocyte modulation reduces spontaneous hippocampal discharges and metabolite changes in an epilepsy mouse model

Abstract Objectives Temporal lobe epilepsy (TLE) is characterized by recurrent, focal seizures, and up to one third of patients are not adequately treated by the current standard of care. This emphasizes the need for continued research into disease mechanisms and potential novel treatment strategies. In TLE, astrocytes transition to a reactive phenotype and we here investigate how modulation of their activity affects spontaneous seizures. Methods We used Gq‐coupled Designer Receptors Exclusively Activated by Designer Drugs (Gq‐DREADD) to target reactive astrocytes in the intrahippocampal kainic acid (IHKA) mouse model for TLE. Through immunohistochemistry, we first verified the astrocyte‐specific expression of Gq‐DREADDs and we quantified astrocytic c‐Fos expression upon Gq‐DREADD activation. Spontaneous inhibitory post‐synaptic currents (sIPSCs) were measured from dentate gyrus granule cells of live hippocampal slices before and after Gq‐DREADD activation. Hippocampal field potentials were monitored in vivo to quantify seizure burden. Finally, metabolic profiling of the hippocampal tissue examined associated effects of Gq‐DREADD activation in epileptic mice. Results Gq‐DREADD activation increased c‐Fos expression in astrocytes but not in the neurons of the epileptic hippocampus and rapidly increased sIPSC in hippocampal slices from epileptic mice. We found a significant reduction in the number of spontaneous hippocampal paroxysmal discharges (HPDs) and overall seizure burden 1 day after Gq‐DREADD modulation of reactive astrocytes. The metabolomics analysis at this time point showed 78 metabolites that were significantly altered in epileptic mice, 11 of which were also altered upon Gq‐DREADD modulation of reactive astrocytes, belonging to several metabolic pathways that have been implicated in epilepsy. Significance Our findings provide converging evidence for a modulatory role of reactive astrocytes in TLE. Gq‐DREADD activation of hippocampal astrocytes suppressed HPDs and induced metabolic shifts, offering insight into astrocyte‐driven mechanisms and potential therapeutic targets.