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

Abstract

SUMMARY Objective 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 (M1R) knockout mice are resistant to PISs, implying that M1R activation disrupts excitation/inhibition balance. Parvalbumin-positive (PV) inhibitory neurons express M1 mAChRs, 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 M1Rs expressed on PV cells contributes to PISs. 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 RosaYFP reporter line. To eliminate M1Rs from PV cells, we generated PV-M1KO 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 WT or PV-M1KO 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-M1KO mice. Finally, compared to WT mice, PV-M1KO mice were associated with reduced severity of PISs. Significance Pilocarpine can directly depolarize PV+ cells via M1R activation but a subset of these cells progress to DB. Our electrophysiological and behavioral results suggest that this mechanism is active during PISs, contributing to a collapse of PV-mediated GABAergic inhibition, dysregulation of excitation/inhibition balance, and increased susceptibility to PISs.

Control of brain state transitions with light

“…1) in order to demonstrate that deep-sleep brain states can be controlled by selectively manipulating muscarinic receptors at their physiological location and context. The oscillatory frequency of the network was greatly increased already at 100 nM Iperoxo, and lead to periods of seizure-like discharges, in agreement with previous studies performed by knockout mice and pilocarpine 39,40 in which pathologic activation of muscarinic acetylcholine receptors induced seizures. Photocontrol of muscarinic signaling was subsequently achieved in vitro and in vivo with the photochromic iperoxo derivative PAI, 23 which is targeted allosterically at M2 subtype receptors ( Fig.…”

“…1B). In addition, at concentrations equal or higher than 100 nM Iperoxo, the oscillatory activity evolved to periods of seizure-like discharges (Fig.1C), 39,40 characterized by low (<1 Hz), delta (1-4 Hz) and alfa (8)(9)(10)(11)(12) Hz) frequencies ( Fig. 1D).…”

Altered Oscillatory Dynamics of CA1 Parvalbumin Basket Cells during Theta–Gamma Rhythmopathies of Temporal Lobe Epilepsy

“…Changes of intrinsic excitability in PV fast-spiking cells due to deficits of Nrg1-Erbb4 signaling reported in TLE could also explain our data (Li et al, 2011). Epileptic PV basket cells are particularly susceptible to entering the depolarizing block (Karlócai et al, 2014; Yi et al, 2015), but our intracellular recordings of identified cells suggest that this is not likely to be the case (Fig. 7 H , I ).…”

Ictal recruitment of anterior nucleus of thalamus in human focal epilepsy

“…The endogenous state that is characterized by theta rhythm is associated with the increased cholinergic activity, seizure severity, and has been found to either promote or prevent a seizure (Colom et al, 2006;Sedigh-Sarvestani et al, 2014;Ewell et al, 2015;Yi et al, 2015).…”