Postsynaptic muscarinic M1 receptors activate prefrontal cortical EEG of C57BL/6J mouse
Abstract
Recent pharmacological studies exploring the functional roles of muscarinic cholinergic receptor (mAChR) subtypes in prefrontal cortex of C57BL/6J (B6) mouse have provided evidence for a presynaptic M2 autoreceptor. The B6 mouse was chosen for these studies because it is a genetically well-characterized model that also provides the genomic background for many genetically modified mice. In addition to increasing ACh release, one functional consequence of pharmacologically blocking the cortical M2 autoreceptor is activation of the contralateral prefrontal cortical EEG. To date, the mechanisms through which M2 autoreceptor antagonism causes cortical EEG activation have not been investigated. The present study tested the hypothesis that, in the B6 mouse, prefrontal cortical ACh activates the contralateral prefrontal EEG via postsynaptic M1 receptors. This hypothesis was tested in 15 mice using in vivo microdialysis delivery of muscarinic antagonists with simultaneous quantification of ACh release, number of 7- to 14-Hz EEG spindles, and fast Fourier transformation analysis of prefrontal EEG. Dialysis delivery of the nonsubtype selective muscarinic antagonist scopolamine (10 nM) significantly (P = 0.01) increased ACh release. Quantitative EEG analysis showed that scopolamine did not alter contralateral prefrontal cortical EEG. To differentiate mAChR subtypes mediating pre- versus postsynaptic responses, additional experiments used muscarinic antagonists with different affinities for the five mAChR subtypes. Microdialysis delivery of 3 nM AF-DX 116, a muscarinic antagonist with relatively high affinity for the M2 and M4 subtypes, significantly (P < 0.01) increased prefrontal cortical ACh release and activated EEG in the contralateral prefrontal cortex. EEG activation was characterized by a significant decrease in number of 7- to 14-Hz EEG spindles (P < 0.0001) and power (Vrms) of EEG slow waves (P < 0.05). Microdialysis delivery of 3 nM AF-DX 116 plus 3 nM pirenzepine, a relatively selective M1 and M4 muscarinic antagonist, also significantly (P < 0.01) increased ACh release but did not decrease the number of EEG spindles and did not change EEG slow waves. The differential EEG and ACh responses to dialysis delivery of the muscarinic antagonists support the conclusion that, in B6 mouse, postsynaptic muscarinic receptors of the M1 subtype are a primary site by which ACh activates the EEG.
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M1/M5 receptors can stimulate dopamine release from striatal synaptosomes and postsynaptic M1/M5 receptors can increase excitability of cortical pyramidal neurons.
“In contrast, M1/M5 receptors can stimulate dopamine (DA) release from striatal synaptosomes (Zhang et al., 2002) and postsynaptic M1/M5 receptors can increase excitability of cortical pyramidal neurons (Douglas et al., 2002; McCormick and Prince, 1985).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Douglas et al., 2002
Presynaptic M2/M4 muscarinic receptors can act as inhibitory autoreceptors on cholinergic terminals and reduce glutamate release from corticocortical and corticostriatal synapses.
“presynaptic M2/M4 mAChRs can act as inhibitory autoreceptors on cholinergic terminals (Douglas et al., 2002; Raiteri et al., 1984) and reduce glutamate release from corticocortical and corticostriatal synapses (Higley et al 2009, Gil et al 1997).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Douglas et al., 2002
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- Authors
- Douglas, C. L., Baghdoyan, H. A., & Lydic, R.
- Affiliations
- Pennsylvania State University (US)
- University of Michigan (US)
- Venue
- Journal of Neurophysiology
- Publisher
- American Physiological Society
- Published
- 2002-12-01
- Volume
- 88
- Issue
- 6
- Pages
- 3003-3009
- ISSN
- 0022-3077 (ISSN-L)
- 1522-1598
- OpenAlex
- W2081589923
- Cited by
- 30
- References
- 45
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2021: 1 · 2020: 2 · 2018: 1 · 2017: 1 · 2015: 1 · 2014: 1 · 2012: 2
- FWCI
- 1.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurophysiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL057120, HL 65272, HL 57120, R01HL065272)
- National Institute of Mental Health (MH-45361)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- M1 muscarinic receptor, prefrontal cortex, cortical EEG, EEG spindles, acetylcholine release, scopolamine, AF-DX 116, pirenzepine, cholinergic neurotransmission, C57BL/6J mice, EEG slow waves, antimuscarinic agents
- MeSH terms
- Animals, Electroencephalography, Male, Mice, Inbred C57BL, Receptors, Muscarinic, Synapses, Prefrontal Cortex, Receptor, Muscarinic M1, Mice
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