The Devil’s in the Details: How to Harness Inhibition for Seizure Control

Paradoxical Effects of Optogenetic Stimulation in Mesial Temporal Lobe Epilepsy Levesque M, Chen LY, Etter G, et al. Ann Neurol. 2019;86(5):714-728. doi:10.1002/ana.25572. Objective: To establish the effects induced by long-term, unilateral stimulation of parvalbumin (PV)-positive interneurons on seizures, interictal spikes, and high-frequency oscillations (80-500 Hz) occurring after pilocarpine-induced status epilepticus (SE)—a proven model of mesial temporal lobe epilepsy (MTLE)—in transgenic mice expressing or not expressing ChR2. Methods: Both PV-ChR2 (n = 6) and PV-Cre (n = 6) mice were treated with pilocarpine to induce SE. Three hours after SE onset, unilateral optogenetic stimulation (450 nm, 25 mW, 20 ms pulses delivered at 8 Hz for 30 seconds every 2 minutes) of CA3 PV-positive interneurons was implemented for 14 continuous days in both groups. Results: Rates of seizures (P <.01), interictal spikes (P <.001), and interictal spikes with fast ripples (250-500 Hz; P <.001) were lower in PV-ChR2 than in PV-Cre mice. Ripples (80-200 Hz) occurring outside of interictal spikes had higher rates in the PV-ChR2 group (P <.01), whereas isolated fast ripples had lower rates (P <.01). However, seizure probability was higher during optogenetic stimulation in PV-ChR2 compared to PV-Cre animals (P <.05). Interpretation: Our findings show that the unilateral activation of CA3 PV-positive interneurons exerts anti-ictogenic effects associated with decreased rates of interictal spikes and fast ripples in this MTLE model. However, PV-positive interneuron stimulation can paradoxically trigger seizures in epileptic animals, supporting the notion that γ-aminobutyric acid type A signaling can also initiate ictogenesis.