Cholinergic modulation of multivesicular release regulates striatal synaptic potency and integration
Open accessAbstract
The pleiotropic actions of neuromodulators on pre- and postsynaptic targets make disentangling the mechanisms underlying regulation of synaptic transmission challenging. In the striatum, acetylcholine modulates glutamate release via activation of muscarinic receptors (mAchRs), although the consequences for postsynaptic signaling are unclear. Using two-photon microscopy and glutamate uncaging to examine individual synapses in the rat striatum, we found that glutamatergic afferents have a high degree of multivesicular release (MVR) in the absence of postsynaptic receptor saturation. We found that mAchR activation decreased both the probability of release and the concentration of glutamate in the synaptic cleft. The corresponding decrease in synaptic potency reduced the duration of synaptic potentials and limited temporal summation of afferent inputs. These findings reveal a mechanism by which a combination of basal MVR and low receptor saturation allow the presynaptic actions of a neuromodulator to control the engagement of postsynaptic nonlinearities and regulate synaptic integration.
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CSDS-induced changes in the activity of NAc cholinergic interneurons contribute to social behavior deficits, perhaps via regulation of local DA release or excitatory synaptic transmission.
“CSDS-induced changes in the activity of NAc cholinergic interneurons also appears to contribute to the social behavior deficits [163], perhaps via regulation of local DA release [164] or excitatory synaptic transmission [165].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [165]
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 Higley et al 2009
Muscarinic acetylcholine receptors reduce the probability of glutamate release from excitatory afferents to the striatum, negatively regulating the ability of these inputs to drive striatal activity.
“In contrast, mAChRs reduce the probability of glutamate release from excitatory afferents to the striatum, negatively regulating the ability of these inputs to drive striatal activity (Barral et al., 1999; Higley et al., 2009; Pakhotin and Bracci, 2007).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Higley et al., 2009
mAChRs at excitatory synapses may decrease presynaptic release.
“mAChRs at excitatory synapses may decrease presynaptic release185 and increase postsynaptic responses186 through independent mechanisms”
From Mechanisms underlying gain modulation in the cortex (2020) · cites this paper as [185]
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- Authors
- Higley, M. J., Soler-Llavina, G. J., & Sabatini, B. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sabatini, Bernardo L
- Venue
- Nature Neuroscience
- Published
- 2009-08-09
- Volume
- 12
- Issue
- 9
- Pages
- 1121-1128
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC2733934
- OpenAlex
- W2106244705
- Cited by
- 110
- References
- 50
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 9 · 2019: 14 · 2018: 10 · 2017: 7 · 2016: 10 · 2015: 5 · 2014: 3 · 2013: 2 · 2012: 9
- FWCI
- 4.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1f31ns049655-01)
- National Institute of Neurological Disorders and Stroke (1 F31 NS049655-01, R01NS046579, F32NS063663, F31 NS049655, R37NS046579, NS046579)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- acetylcholine, muscarinic receptors, multivesicular release, striatum, glutamate release, synaptic potentiation, synaptic integration, temporal summation, glutamate uncaging, two-photon microscopy, dendritic nonlinearities
- MeSH terms
- Animals, Calcium, Corpus Striatum, Membrane Potentials, Synaptic Transmission, Probability, Receptors, Muscarinic, Synapses, Synaptic Vesicles, Time Factors, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Presynaptic Terminals, Glutamic Acid, Excitatory Postsynaptic Potentials, Calcium Channels, N-Type, Dendritic Spines, Rats, In Vitro Techniques
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