Optogenetic Stimulation of Insular Parvalbumin-Positive Interneurons Reveals CA3 Resonant Properties and Rebound Seizure Susceptibility

Seizures in mesial temporal lobe epilepsy (MTLE) can spread to the insular cortex (IC) due to its connections with hippocampal and para-hippocampal areas. The contribution of specific cell types in the IC to ictogenesis remains however unclear. Therefore, we analyzed in the pilocarpine model of MTLE the effects of optogenetic activation of IC parvalbumin (PV)-positive interneurons on CA3 field activity. Light pulses were delivered at 0.5 Hz (300 s ON, 600 s OFF) in IC, between day 4 and 14 after status epilepticus in PV-ChR2 mice. During interictal periods, this procedure evoked CA3 field responses characterized by 5 Hz oscillations, which likely mirrored heightened inhibitory activity as suggested by a shift toward higher theta/beta ratio and a more negative spectral exponent. Analysis of ictal activity revealed that seizures occurred at higher rates during days of stimulation (day 4-14) compared to days with no stimulation (day 15-24) (p < 0.05). During the 300 s optogenetic stimulation cycle, seizures occurred at high rates between 301 and 502 s after the end of stimulation (p < 0.05). Our findings suggest that during the interictal phase, the synchronized activation of PV-positive interneurons in the IC imposes a GABAergic drive that, through post-inhibitory rebound mechanisms, entrains the CA3 network into a 5 Hz resonant oscillation. During states of pathological hyperexcitability, this synchronized rebound activity reaches a threshold that converts a rhythmic oscillation into a seizure. Stimulation of the IC could bias the hippocampal network toward 5 Hz oscillatory states and promote ictogenesis via inhibitory-rebound synchronization.