Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy.
Title | Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Lévesque M, Chen L-Y, Etter G, Shiri Z, Wang S, Williams S, Avoli M |
Journal | Ann Neurol |
Volume | 86 |
Issue | 5 |
Pagination | 714-728 |
Date Published | 2019 Nov |
ISSN | 1531-8249 |
Abstract | OBJECTIVE: To establish the effects induced by long-term, unilateral stimulation of parvalbumin (PV)-positive interneurons on seizures, interictal spikes, and high-frequency oscillations (80-500Hz) 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: 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 (450nm, 25mW, 20-millisecond pulses delivered at 8Hz 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 < 0.01), interictal spikes (p < 0.001), and interictal spikes with fast ripples (250-500Hz) (p < 0.001) were lower in PV-ChR2 than in PV-Cre mice. Ripples (80-200Hz) occurring outside of interictal spikes had higher rates in the PV-ChR2 group (p < 0.01), whereas isolated fast ripples had lower rates (p < 0.01). However, seizure probability was higher during optogenetic stimulation in PV-ChR2 compared to PV-Cre animals (p < 0.05).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. ANN NEUROL 2019;86:714-728. |
DOI | 10.1002/ana.25572 |
Alternate Journal | Ann. Neurol. |
PubMed ID | 31393618 |
Grant List | MOP119340 / / CIHR / Canada MOP130328 / / CIHR / Canada PJT153310 / / CIHR / Canada / / Savoy Foundation / MOP119340 / / CIHR / Canada MOP130328 / / CIHR / Canada PJT153310 / / CIHR / Canada |