Research article summary (published 3 Aug 2009):

M1 receptors mediate cholinergic modulation of excitability in neocortical pyramidal neurons.

Full Abstract

ACh release into the rodent prefrontal cortex is predictive of successful performance of cue detection tasks, yet the cellular mechanisms underlying cholinergic modulation of cortical function are not fully understood. Prolonged ("tonic") muscarinic ACh receptor (mAChR) activation increases the excitability of cortical pyramidal neurons, whereas transient ("phasic") mAChR activation generates inhibitory and/or excitatory responses, depending on neuron subtype. These cholinergic effects result from activation of "M1-like" mAChRs (M1, M3, and M5 receptors), but the specific receptor subtypes involved are not known. We recorded from cortical pyramidal neurons from wild-type mice and mice lacking M1, M3, and/or M5 receptors to determine the relative contribution of M1-like mAChRs to cholinergic signaling in the mouse prefrontal cortex. Wild-type neurons in layer 5 were excited by tonic mAChR stimulation, and had biphasic inhibitory followed by excitatory, responses to phasic ACh application. Pyramidal neurons in layer 2/3 were substantially less responsive to tonic and phasic cholinergic input. Cholinergic effects were largely absent in neurons from mice lacking M1 receptors, but most were robust in neurons lacking M3, M5, or both M3 and M5 receptors. The exception was tonic cholinergic suppression of the afterhyperpolarization in layer 5 neurons, which was absent in cells lacking either M1 or M3 receptors. Finally, we confirm a role for M1 receptors in behavior by demonstrating cue detection deficits in M1-lacking mice. Together, our results demonstrate that M1 receptors facilitate cue detection behaviors and are both necessary and sufficient for most direct effects of ACh on pyramidal neuron excitability.

Author information

Author/s: Gulledge, Allan T (AT); Bucci, David J (DJ); Zhang, Sunny S (SS); Matsui, Minoru (M); Yeh, Hermes H (HH);

Affiliation: Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire 03756-0001, USA. allan.gulledge(-atsign-)dartmouth.edu.

Grants: R01 AA014689 (Agency:NIAAA NIH HHS) ; R01 MH83806 (Agency:NIMH NIH HHS) ; R01 NS048603 (Agency:NINDS NIH HHS)

Journal and publication information

Publication Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci), published in United States. (Language: eng)

Reference: 2009-Aug; vol 29 (issue 31) : pp 9888-902

Dates: Created 2009/08/06; Completed 2009/08/21; Revised 2009/09/17;

PMID: 19657040, status: MEDLINE (last retrieval date: 9/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Action Potentials - drug effects Analysis of Variance Animals Carbachol - pharmacology Cholinergic Agonists - pharmacology Conditioning, Classical - physiology Cues Mice Mice, Inbred C57BL

Mice, Inbred C57BL Mice, Knockout Motor Activity - physiology Patch-Clamp Techniques Prefrontal Cortex - drug effects; physiology Pyramidal Cells - drug effects; physiology Receptor, Muscarinic M1 - agonists; genetics; metabolism Receptor, Muscarinic M3 - agonists; genetics; metabolism Receptor, Muscarinic M5 - agonists; genetics; metabolism

Associated Chemicals: Cholinergic Agonists (0) ; Receptor, Muscarinic M1 (0) ; Receptor, Muscarinic M3 (0) ; Receptor, Muscarinic M5 (0) ; Carbachol (51-83-2)

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