Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum
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The neurotransmitter glutamate is released by excitatory projection neurons throughout the brain. However, non-glutamatergic cells, including cholinergic and monoaminergic neurons, express markers that suggest that they are also capable of vesicular glutamate release. Striatal cholinergic interneurons (CINs) express the Type-3 vesicular glutamate transporter (VGluT3), although whether they form functional glutamatergic synapses is unclear. To examine this possibility, we utilized mice expressing Cre-recombinase under control of the endogenous choline acetyltransferase locus and conditionally expressed light-activated Channelrhodopsin2 in CINs. Optical stimulation evoked action potentials in CINs and produced postsynaptic responses in medium spiny neurons that were blocked by glutamate receptor antagonists. CIN-mediated glutamatergic responses exhibited a large contribution of NMDA-type glutamate receptors, distinguishing them from corticostriatal inputs. CIN-mediated glutamatergic responses were insensitive to antagonists of acetylcholine receptors and were not seen in mice lacking VGluT3. Our results indicate that CINs are capable of mediating fast glutamatergic transmission, suggesting a new role for these cells in regulating striatal activity.
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Glutamate release onto SPNs activates ionotropic glutamate receptors with distinct AMPA/NMDA ratios compared with cortico-striatal synapses, suggesting distinct plasticity rules.
“Glutamate release onto SPNs activates postsynaptic ionotropic glutamate receptors with distinct AMPA/NMDA ratios compared with cortico-striatal synapses, suggesting distinct plasticity rules from these disparate inputs.60”
From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [60]
Striatal cholinergic interneurons cotransmit Ach and glutamate locally onto spiny projection neurons and dopaminergic axonal terminals.
“Striatal cholinergic interneurons (CINs) cotransmit Ach and glutamate locally onto spiny projection neurons (SPNs) 60 and dopaminergic axonal terminals.[61][62][63]”
From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [60]
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- Authors
- Higley, M. J., Gittis, A. H., Oldenburg, I. A., Balthasar, N., Seal, R. P., Edwards, R. H., Lowell, B. B., Kreitzer, A. C., & Sabatini, B. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Sabatini, Bernardo L.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-04-22
- Volume
- 6
- Issue
- 4
- Pages
- e19155
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3081336
- OpenAlex
- W2137833675
- Cited by
- 175
- References
- 35
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 10 · 2022: 14 · 2021: 11 · 2020: 14 · 2019: 10 · 2018: 12 · 2017: 16 · 2016: 14 · 2015: 16 · 2014: 12 · 2013: 10 · 2012: 13
- FWCI
- 5.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- KiltHub Repository (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion)
- KiltHub Repository (cc-by)
- Funders
- Howard Hughes Medical Institute
- W. M. Keck Foundation
- Parkinson's Disease Foundation
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (DK057521, DK046200, DA10154, NS046579)
- National Institute of Mental Health (F32MH068085, MH50712, R01MH050712, R37MH050712, F31MH093026)
- National Institute on Drug Abuse (P01DA010154, DA-10154)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057521, R01DK075632, P30DK046200, DK075632)
- National Institute of Neurological Disorders and Stroke (NS064984, R01NS046579, F32NS063663, R01NS064984, R37NS046579, NS063663, 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
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- cholinergic interneurons, striatum, VGLUT3, glutamatergic neurotransmission, medium spiny neurons, NMDA receptor, choline acetyltransferase, channelrhodopsin-2, optogenetic stimulation
- MeSH terms
- Channelrhodopsins, Central Nervous System Stimulants, Animals, Corpus Striatum, Evoked Potentials, Female, Interneurons, Male, Mecamylamine, Picrotoxin, Receptors, Cholinergic, Scopolamine, Receptors, N-Methyl-D-Aspartate, Amino Acid Transport Systems, Acidic, Mice
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