Optogenetic activation of septal inhibitory cells abates focal seizures

Emerging evidence suggests that the medial septum can control seizures occurring in focal epileptic disorders, thus representing a therapeutic target. Therefore, we investigated whether continuous optogenetic activation of inhibitory parvalbumin (PV)-positive interneurons in the medial septum can reduce the occurrence of spontaneous seizures in the pilocarpine model of mesial temporal lobe epilepsy (MTLE). Light pulses (450 nm, 25 mW, 20-ms pulse duration) were delivered at 0.5 Hz (5 min ON, 10 min OFF) with a laser diode fiber light source between day 8 and day 12 after status epilepticus (SE) in PV-ChR2 mice (n = 8). Seizure rates were significantly lower during time periods of optogenetic stimulation (days 8-12) compared with before implementation of optogenetics (days 4-7) (P < 0.05). Moreover, between day 13 and day 21 after SE seizure rates were still significantly lower compared with before optogenetic stimulation (i.e., between day 4 and day 7) (P < 0.05). No seizures were recorded between day 10 and day 12 in all animals, and no seizures occurred up to 3 days after the end of optogenetic stimulation (days 13-15). Our findings indicate that activation of PV interneurons in the medial septum abates seizures in the pilocarpine model of MTLE. Moreover, the persisting anti-ictogenic effects suggest that stimulation of the medial septum could alter the progression of MTLE.NEW & NOTEWORTHY The medial septum could represent a therapeutic target to treat patients with focal epilepsy. In this study, we show that optogenetic activation of inhibitory parvalbumin-positive interneurons in the medial septum can block spontaneous seizures and prevents their reoccurrence for ∼5 days after the end of stimulation. Our findings suggest that the anti-ictogenic effects induced by stimulation of the medial septum could also alter the progression of mesial temporal lobe epilepsy.