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Muscarinic excitation of parvalbumin‐positive interneurons contributes to the severity of pilocarpine‐induced seizures
Author(s) -
Yi Feng,
DeCan Evan,
Stoll Kurt,
Marceau Eric,
Deisseroth Karl,
Lawrence J. Josh
Publication year - 2015
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12883
Subject(s) - pilocarpine , muscarinic acetylcholine receptor , depolarization , parvalbumin , knockout mouse , muscarinic agonist , endocrinology , medicine , neuroscience , agonist , chemistry , biology , epilepsy , receptor
Summary Objective A common rodent model in epilepsy research employs the muscarinic acetylcholine receptor (m AC hR) agonist pilocarpine, yet the mechanisms underlying the induction of pilocarpine‐induced seizures ( PIS s) remain unclear. Global M 1 mAChR (M 1 R) knockout mice are resistant to PISs, implying that M 1 R activation disrupts excitation/inhibition balance. Parvalbumin‐positive ( PV ) inhibitory neurons express M 1 Rs, participate in cholinergically induced oscillations, and can enter a state of depolarization block ( DB ) during epileptiform activity. Here, we test the hypothesis that pilocarpine activation of M 1 Rs expressed on PV cells contributes to PIS s. Methods CA1 PV cells in PV ‐ CRE mice were visualized with a floxed YFP or hM3Dq‐mCherry adeno‐associated virus, or by crossing PV ‐ CRE mice with the Rosa YFP reporter line. To eliminate M 1 Rs from PV cells, we generated PV‐M 1 knockout (KO) mice by crossing PV‐CRE and floxed M 1 mice. Action potential (AP) frequency was monitored during application of pilocarpine (200 μ m ). In behavioral experiments, locomotion and seizure symptoms were recorded in wild‐type ( WT ) or PV‐M 1 KO mice during PISs. Results Pilocarpine significantly increased AP frequency in CA1 PV cells into the gamma range. In the continued presence of pilocarpine, a subset (5/7) of PV cells progressed to DB, which was mimicked by hM3Dq activation of Gq‐receptor signaling. Pilocarpine‐induced depolarization, AP firing at gamma frequency, and progression to DB were prevented in CA1 PV cells of PV‐M 1 KO mice. Finally, compared to WT mice, PV‐M 1 KO mice were associated with reduced severity of PISs. Significance Pilocarpine can directly depolarize PV + cells via M 1 R activation, but a subset of these cells progress to DB . Our electrophysiologic and behavioral results suggest that this mechanism is active during PIS s, contributing to a collapse of PV ‐mediated γ‐aminobutyric acid ( GABA )ergic inhibition, dysregulation of excitation/inhibition balance, and increased susceptibility to PIS s.