Depolarized GABAergic Signaling in Subicular Microcircuits Mediates Generalized Seizure in Temporal Lobe Epilepsy

Secondary generalized seizure (sGS) is a major source of disability in temporal lobe epilepsy (TLE) with unclear cellular/circuit mechanisms. Here we found that clinical TLE patients with sGS showed reduced volume specifically in the subiculum compared with those without sGS. Further, using optogenetics and extracellular electrophysiological recording in mouse models, we found that photoactivation of subicular GABAergic neurons retarded sGS acquisition by inhibiting the firing of pyramidal neurons. Once sGS had been stably acquired, photoactivation of GABAergic neurons aggravated sGS expression via depolarized GABAergic signaling. Subicular parvalbumin, but not somatostatin subtype GABAergic, neurons were easily depolarized in sGS expression. Finally, photostimulation of subicular pyramidal neurons genetically targeted with proton pump Arch, rather than chloride pump NpHR3.0, alleviated sGS expression. These results demonstrated that depolarized GABAergic signaling in subicular microcircuit mediates sGS in TLE. This may be of therapeutic interest in understanding the pathological neuronal circuitry underlying sGS. [Display omitted] •The volume of the subiculum was additionally reduced in TLE patients with sGS•Subicular GABAergic neurons retard sGS acquisition, but aggravate sGS expression•Depolarized GABAergic signaling in subicular microcircuit mediates sGS expression•Parvalbumin, but not somatostatin, neurons are easily depolarized in sGS expression The subiculum is crucially involved in spreading and generalizing hippocampal seizures. Wang et al. demonstrated depolarized GABAergic signaling caused by the change of chloride transporters in subicular microcircuit mediates secondary generalized seizures in temporal lobe epilepsy in vivo.