Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy.

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.

• Authors: Maxime Lévesque, Li-Yuan Chen, Guillaume Etter, Zahra Shiri, Siyan Wang, Sylvain Williams, Massimo Avoli
• Journal: Annals of neurology (Ann Neurol) Vol. 86 Issue 5 Pg. 714-728 (11 2019) ISSN: 1531-8249 [Electronic] United States
• PMID: 31393618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 American Neurological Association.

Chemical References

• Convulsants
• Pilocarpine

Topics

• Animals
• CA3 Region, Hippocampal (physiopathology)
• Convulsants (toxicity)
• Epilepsy, Temporal Lobe (chemically induced, physiopathology)
• Interneurons (physiology)
• Male
• Mice
• Mice, Transgenic
• Optogenetics
• Pilocarpine (toxicity)
• Seizures (chemically induced, physiopathology)