Muscarinic excitation of parvalbumin-positive interneurons contributes to the severity of pilocarpine-induced seizures EPILEPSIA Yi, F., DeCan, E., Stoll, K., Marceau, E., Deisseroth, K., Lawrence, J. J. 2015; 56 (2): 297-309

Abstract

A 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 M1 mAChR (M1 R) knockout mice are resistant to PISs, implying that M1 R activation disrupts excitation/inhibition balance. Parvalbumin-positive (PV) inhibitory neurons express M1 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 M1 Rs expressed on PV cells contributes to PISs.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 RosaYFP reporter line. To eliminate M1 Rs from PV cells, we generated PV-M1 knockout (KO) mice by crossing PV-CRE and floxed M1 mice. Action potential (AP) frequency was monitored during application of pilocarpine (200 µm). In behavioral experiments, locomotion and seizure symptoms were recorded in wild-type (WT) or PV-M1 KO mice during PISs.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-M1 KO mice. Finally, compared to WT mice, PV-M1 KO mice were associated with reduced severity of PISs.Pilocarpine can directly depolarize PV+ cells via M1 R 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.

View details for DOI 10.1111/epi.12883

View details for Web of Science ID 000350146300028

View details for PubMedID 25495999

View details for PubMedCentralID PMC4339470