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M muscarinic activation induces long-lasting increase in intrinsic excitability of striatal projection neurons.

Lv X, Dickerson JW, Rook JM, Lindsley CW, Conn PJ, Xiang Z
Neuropharmacology. 2017 118: 209-222

PMID: 28336323 · PMCID: PMC5501169 · DOI:10.1016/j.neuropharm.2017.03.017

The dorsolateral striatum is critically involved in movement control and motor learning. Striatal function is regulated by a variety of neuromodulators including acetylcholine. Previous studies have shown that cholinergic activation excites striatal principal projection neurons, medium spiny neurons (MSNs), and this action is mediated by muscarinic acetylcholine subtype 1 receptors (M) through modulating multiple potassium channels. In the present study, we used electrophysiology techniques in conjunction with optogenetic and pharmacological tools to determine the long-term effects of striatal cholinergic activation on MSN intrinsic excitability. A transient increase in acetylcholine release in the striatum by optogenetic stimulation resulted in a long-lasting increase in excitability of MSNs, which was associated with hyperpolarizing shift of action potential threshold and decrease in afterhyperpolarization (AHP) amplitude, leading to an increase in probability of EPSP-action potential coupling. The M selective antagonist VU0255035 prevented, while the M selective positive allosteric modulator (PAM) VU0453595 potentiated the cholinergic activation-induced persistent increase in MSN intrinsic excitability, suggesting that M receptors are critically involved in the induction of this long-lasting response. This M receptor-dependent long-lasting change in MSN intrinsic excitability could have significant impact on striatal processing and might provide a novel mechanism underlying cholinergic regulation of the striatum-dependent motor learning and cognitive function. Consistent with this, behavioral studies indicate that potentiation of M receptor signaling by VU0453595 enhanced performance of mice in cue-dependent water-based T-maze, a dorsolateral striatum-dependent learning task.

Copyright © 2017. Published by Elsevier Ltd.

MeSH Terms (21)

Acetylcholine Action Potentials Animals Channelrhodopsins Choline O-Acetyltransferase Cholinergic Agents Corpus Striatum Cues Excitatory Amino Acid Antagonists Excitatory Postsynaptic Potentials Female Gene Expression Regulation Learning Male Mice Mice, Inbred C57BL Mice, Transgenic Motor Activity Neurons Photic Stimulation Receptor, Muscarinic M1

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