Preferential Localization of Muscarinic M1Receptor on Dendritic Shaft and Spine of Cortical Pyramidal Cells and Its Anatomical Evidence for Volume Transmission
Open accessAbstract
Acetylcholine (ACh) plays important roles for higher brain functions, including arousal, attention, and cognition. These effects are mediated largely by muscarinic acetylcholine receptors (mAChRs). However, it remains inconclusive whether the mode of ACh-mAChR signaling is synaptic, so-called “wired,” transmission mediated by ACh released into the synaptic cleft, or nonsynaptic, so-called “volume,” transmission by ambient ACh. To address this issue, we examined cellular and subcellular distribution of M 1, the most predominant mAChR subtype in the cerebral cortex and hippocampus, and pursued its anatomical relationship with cholinergic varicosities in these regions of adult mice. M 1 was highly expressed in glutamatergic pyramidal neurons, whereas it was low or undetectable in various GABAergic interneuron subtypes. M 1 was preferentially distributed on the extrasynaptic membrane of pyramidal cell dendrites and spines. Cholinergic varicosities often made direct contact to pyramidal cell dendrites and synapses. At such contact sites, however, synapse-like specialization was infrequent, and no particular accumulation was found at around contact sites for both M 1 and presynpatic active zone protein Bassoon. These features contrasted with those of the glutamatergic system, in which AMPA receptor GluA2 and metabotropic receptor mGluR5 were recruited to the synaptic or perisynaptic membrane, respectively, and Bassoon was highly accumulated in the presynaptic terminals. These results suggest that M 1 is so positioned to sense ambient ACh released from cholinergic varicosities at variable distances, and to enhance the synaptic efficacy and excitability of pyramidal cells. These molecular–anatomical arrangements will provide the evidence for volume transmission, at least in M 1-mediated cortical cholinergic signaling.
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Extremely high concentrations of ACh in the extrasynaptic space stimulate extra-synaptic mAChRs and nAChRs to a degree and at locations that may not be achieved without an AChE inhibitor.
“Furthermore, the presence of extremely high concentrations of ACh in the extrasynaptic space (volume transmission) results in the stimulation of extra-synaptic mAChRs (Yamasaki et al, 2010) and nAChRs, to a degree and at locations that may not be achieved in the absence of an AChE inhibitor (Sarter et al, 2009a).”
From Modes and models of forebrain cholinergic neuromodulation of cognition (2011) · cites this paper as Yamasaki et al, 2010
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- Authors
- Yamasaki, M., Matsui, M., & Watanabe, M.
- Affiliations
- Hokkaido University (JP)
- Corresponding author
- Watanabe, Masahiko
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-03-24
- Volume
- 30
- Issue
- 12
- Pages
- 4408-4418
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6634497
- OpenAlex
- W2079169622
- Cited by
- 203
- References
- 63
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 4 · 2023: 9 · 2022: 10 · 2021: 16 · 2020: 13 · 2019: 9 · 2018: 18 · 2017: 6 · 2016: 11 · 2015: 16 · 2014: 17 · 2013: 20 · 2012: 20
- FWCI
- 8.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Hokkaido University Collection of Scholarly and Academic Papers (Hokkaido University) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (17023001, 19100005)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- M1 muscarinic receptor, volume transmission, acetylcholine, cortical pyramidal neurons, dendritic spines, bassoon, active zone, glutamatergic synapses, mGluR5, GluA2, hippocampus, cerebral cortex, cholinergic neurotransmission
- MeSH terms
- Animals, Cerebral Cortex, Dendrites, Glutamate Decarboxylase, Hippocampus, Mice, Inbred C57BL, Microtubule-Associated Proteins, Neuropeptide Y, RNA, Messenger, Receptors, N-Methyl-D-Aspartate, Microscopy, Immunoelectron, Pyramidal Cells, Receptors, AMPA, Mice, Knockout, Membrane Transport Proteins, Receptor, Muscarinic M1, Microscopy, Electron, Transmission, Dendritic Spines, Vesicular Acetylcholine Transport Proteins, Vesicular Glutamate Transport Protein 1, Mice, Nitric Oxide Synthase Type I, S100 Calcium Binding Protein G, Calbindin 2
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