Bilateral optogenetic activation of inhibitory cells favors ictogenesis

Abstract

Mesial temporal lobe epilepsy (MTLE) is the most common type of focal refractory epilepsy and is characterized by recurring seizures that are often refractory to medication. Since parvalbumin-positive (PV) interneurons were recently shown to play significant roles in ictogenesis, we established here how bilateral optogenetic stimulation of these interneurons in the hippocampus CA3 regions modulates seizures, interictal spikes and high-frequency oscillations (HFOs; ripples: 80–200 Hz, fast ripples: 250–500 Hz) in the pilocarpine model of MTLE. Bilateral optogenetic stimulation of CA3 PV-positive interneurons at 8 Hz (lasting 30 s, every 2 min) was implemented in PV-ChR2 mice for 8 consecutive days starting on day 7 (n = 8) or on day 13 (n = 6) after pilocarpine-induced status epilepticus (SE). Seizure occurrence was higher in both day 7 and day 13 groups of PV-ChR2 mice during periods of optogenetic stimulation (“ON”), compared to when stimulation was not performed (“OFF”) (day 7 group = p < 0.01, day 13 group = p < 0.01). In the PV-ChR2 day 13 group, rates of seizures (p < 0.05), of interictal spikes associated with fast ripples (p < 0.01), and of isolated fast ripples (p < 0.01) during optogenetic stimulations were significantly higher than in the PV-ChR2 day 7 group. Our findings reveal that bilateral activation of PV-interneurons in the hippocampus (leading to a presumptive increase in GABA signaling) favors ictogenesis. These effects may also mirror the neuropathological changes that occur over time after SE in this animal model.