Muscarinic excitation of parvalbumin-positive interneurons contributes to the severity of pilocarpine-induced seizures

作者：Yi Feng; DeCan Evan; Stoll Kurt; Marceau Eric; Deisseroth Karl; Lawrence J Josh^*

来源：Epilepsia, 2015, 56(2): 297-309.

DOI：10.1111/epi.12883

• Pilocarpine
• Muscarinic
• Acetylcholine
• Hippocampus
• Seizures

ObjectiveA common rodent model in epilepsy research employs the muscarinic acetylcholine receptor (mAChR) agonist pilocarpine, yet the mechanisms underlying the induction of pilocarpine-induced seizures (PISs) remain unclear. Global M-1 mAChR (M1R) knockout mice are resistant to PISs, implying that M1R 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 PISs.
MethodsCA1 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 RosaYFP 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 (200m). In behavioral experiments, locomotion and seizure symptoms were recorded in wild-type (WT) or PV-M1KO mice during PISs.
ResultsPilocarpine 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-M1KO mice. Finally, compared to WT mice, PV-M1KO mice were associated with reduced severity of PISs.
SignificancePilocarpine can directly depolarize PV+ cells via M1R activation, but a subset of these cells progress to DB. Our electrophysiologic and behavioral results suggest that this mechanism is active during PISs, contributing to a collapse of PV-mediated -aminobutyric acid (GABA)ergic inhibition, dysregulation of excitation/inhibition balance, and increased susceptibility to PISs.

• 出版日期2015-2