Cited by 175Neuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on BehaviorDeep Brain Stimulation and Movement Disorders

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Cholinergic Interneurons Mediate Fast VGluT3-Dependent Glutamatergic Transmission in the Striatum

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Higley, Michael J., Gittis, Aryn H., Oldenburg, Ian A., Balthasar, Nina, Seal, Rebecca P., Edwards, Robert H., Lowell, Bradford B., Kreitzer, Anatol C., Sabatini, Bernardo L.·2011·PLoS ONE

DOI 10.1371/journal.pone.0019155PMC PMC3081336

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Abstract

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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Figure 1 ChR2-mediated activation of striatal cholinergic interneurons. (Ai) Confocal image of mCherry-positive ChR2-expressing neurons in the dorsal striatum of a ChAT-IRES-Cre mouse injected with AAV encoding DFI-ChR2-mCherry. (Aii) Fluorescence immunohistochemical staining for ChAT reveals cholinergic neurons. (Aiii) Merged image. (B) inset, Schematic diagram of the recording conditions: cell-attached recordings were made from ChR2-expressing CINs (red) in the dorsal striatum and blue light was delivered to the surrounding area (blue circle) through the microscope objective. main panel, Example action potential recorded in cell-attached mode from a ChR2-expressing CIN evoked by a 4 ms pulse of 473 nm light.CC BY · PubMed Central

Figure 2 Light-evoked CIN action potentials evoke glutamatergic responses in MSNs. (A) inset, Schematic diagram of the recording conditions: whole-cell recordings were made from MSNs that neighbored ChR2-expressing CINs (red). The blue circle indicates the region stimulated by blue light. main panel, Example EPSP recorded in an MSN in response to a 4 ms light pulse (blue bar). (B) Amplitudes of light-evoked EPSPs in the presence of antagonists of GABAA (Picrotoxin, Ptx), muscarinic (Scopolamine, Scop), and nicotinic (Mecamylamine, Mec) receptors and following application of the AMPA/kainate glutamate receptor antagonist NBQX. (C) Example of light evoked (blue bar) CIN-mediated EPSCs in a voltage-clamped MSN at holding potentials of −70 and +40 mV demonstrating the large current that is visible more than 100 ms after the light pulse at +40 mV. The amplitudes of the rapid −70 and prolonged +40 mV EPSC components were measured in the periods indicated by the gray bars. (D) Confocal image of mCherry-positive ChR2-expressing fibers in the motor cortex, white matter (WM) and underlying striatum (Str). Large bundles of corticofugal fibers (white arrowheads) and diffuse small axonal collaterals are visible throughout the dorsolateral striatum. Scale bar 200 µm. (E) inset, Schematic diagram of the recording conditions: whole-cell recordings were made from MSNs neighboring ChR2-expressing corticostriatal fibers (red), and blue light was delivered to the region indicated by the blue circle. main panel, Example EPSCs recorded in an MSN in response to a blue light pulse at the indicated holding potentials. (F) left, Average amplitudes of light-evoked EPSCs measured in MSNs held at either −70 or +40 mV in response to ChR2-mediated activation of either CINs or corticostriatal fibers (Cx). right, Average ratio of +40/−70 mV current amplitudes measured following ChR2-mediated activation of either CINs or corticostriatal fibers.CC BY · PubMed Central

Figure 3 CIN-mediated glutamatergic currents in MSNs require VGluT3 expression. (A) Example light-evoked EPSCs at 32–34°C in an MSN held at −70 or +40 mV in an acute striatal slice of a DFI-ChR2-mCherry AAV injected ChAT-IRES-Cre mouse. (B) As in Panel A, showing recordings at 32–34°C obtained from an MSN in an acute slice of a DFI-ChR2-mCherry AAV injected GM60 mouse that expresses Cre under control of a BAC spanning the ChAT genomic locus. (C) As in Panel B, showing failures to evoke EPSCs in an MSN of a DFI-ChR2-mCherry AAV injected GM60; VGluT3−/− mouse. (D) Average light-evoked EPSC amplitudes measured in MSNs at holding potentials of −70 and +40 mV in acute slices prepared from mice of the indicated genotypes.CC BY · PubMed Central

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Background
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“, 2020) whereas others showed the abolition of a glutamatergic ionotropic currents (Varga et al., 2009; Higley et al., 2011).”
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VGLUT3 Ablation Differentially Modulates Glutamate Receptor Densities in Mouse Brain
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“Both NMDAR and AMPAR mediate VGLUT3 signaling in different brain areas (Higley et al., 2011; Nelson et al., 2014; Wang et al., 2019).”
BackgroundInfluential
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“Given the recent debates regarding the role of cholinergic signaling itself, as opposed to other co-released neurotransmitters in the striatum and cortex 61 – 63 , we next determined the neurotransmitter identity of these photo-evoked currents.”
Generation of BAC Transgenic Mice for Functional Analysis of Neural Circuits
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“As CINs release both glutamate and acetylcholine [56], the diminished cCPP observed by Witten et al [35] when inhibiting CINs could be mediated by decreased CIN glutamate release, not ACh release, which reconciles those results with the conflicting findings from Guzman et al [52] who found no…”
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“2c , left ), although a small, yet significant, delayed peak persisted at both dosages, pointing to a non-cholinergic CIN messenger 45–47 that can evoke DA release in vivo .”
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CRISPR/CAS9-MEDIATED LOSS OF VESICULAR GLUTAMATE TRANSPORTER IN SEROTONIN NEURONS OF THE DORSAL RAPHE NUCLEUS LEADS TO SYNAPTIC CHANGES AND ANXIETY-LIKE BEHAVIORSPreprint
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Ztaou, S. (2016) · theses.fr (ABES) · doi:10.70675/82c2ea24zaacdz49cfz88e0z86d5151777b4
Regulation of the protein synthesis machinery in the striatum
Biever, A. (2016) · theses.fr (ABES) · doi:10.70675/d51e3b2cz4ba2z4930z8686z2d89c7f3949d
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Laverne, G. (2020) · theses.fr (ABES) · doi:10.70675/d58a850bz5ba6z4b96z946fza210d8730737
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Braine, A. (2023) · theses.fr (ABES) · doi:10.70675/fa2ba80bz6788z4fdczbdf5zebda852ad621
The role of VGLUT3 in behaviour, with a focus on VGLUT3 positive neurons of the median raphe region
Fazekas, C. L. (2023) · theses.fr (ABES) · doi:10.70675/517bbedbz9f8ez4541z9f7dzead2ac6bb84e
Basal ganglia
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The VGLUT3-p.T8I Mutation Alters Striatal Acetylcholine Dynamics in Response to Social Stressors and Drives Selective Social Avoidance in Male MicePreprint
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“This dual neurotransmitter phenotype arises from the expression of both the vesicular acetylcholine transporter (VAChT) and the vesicular glutamate transporter 3 (VGLUT3) [25–28].”

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: Higley, Michael J.
Gittis, Aryn H.
Oldenburg, Ian A.
Seal, Rebecca P.
Edwards, Robert H.
Lowell, Bradford B.
Kreitzer, Anatol C.
Sabatini, Bernardo L.
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2011-04-22
Volume: 6
Issue: 4
Pages: e19155
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0019155
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
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
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 › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
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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Cholinergic Interneurons Mediate Fast VGluT3-Dependent Glutamatergic Transmission in the Striatum

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