Paradoxical network excitation by glutamate release from VGluT3+ GABAergic interneurons
Open accessAbstract
In violation of Dale’s principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter three and cholecystokinin expressing cortical interneurons (CCK+VGluT3+INTs) has prompted speculation of GABA/glutamate corelease from these cells for almost two decades despite a lack of direct evidence. We unequivocally demonstrate CCK+VGluT3+INT-mediated GABA/glutamate cotransmission onto principal cells in adult mice using paired recording and optogenetic approaches. Although under normal conditions, GABAergic inhibition dominates CCK+VGluT3+INT signaling, glutamatergic signaling becomes predominant when glutamate decarboxylase (GAD) function is compromised. CCK+VGluT3+INTs exhibit surprising anatomical diversity comprising subsets of all known dendrite targeting CCK+ interneurons in addition to the expected basket cells, and their extensive circuit innervation profoundly dampens circuit excitability under normal conditions. However, in contexts where the glutamatergic phenotype of CCK+VGluT3+INTs is amplified, they promote paradoxical network hyperexcitability which may be relevant to disorders involving GAD dysfunction such as schizophrenia or vitamin B6 deficiency.
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The Glut-GABA clusters include four clusters in the isocortex and hippocampus and three clusters in globus pallidus, internal segment, which probably correspond to previously well-characterized glutamate-GABA co-releasing neuronal types in these regions.
“They include four clusters in the isocortex and hippocampus and three clusters in globus pallidus, internal segment (GPi), which probably correspond to previously well-characterized glutamate–GABA co-releasing neuronal types in these regions41,42.”
From A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain (2023) · cites this paper as [42]
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PYRIDOXINE DEFICIENCY AND BRAIN AMINO ACIDS
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A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain
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- Authors
- Pelkey, K. A., Calvigioni, D., Fang, C., Vargish, G., Ekins, T., Auville, K., Wester, J. C., Lai, M., Mackenzie-Gray Scott, C., Yuan, X., Hunt, S., Abebe, D., Xu, Q., Dimidschstein, J., Fishell, G., Chittajallu, R., & McBain, C. J.
- Affiliations
- National Institutes of Health (US)
- <italic>Eunice Kennedy Shriver</italic> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
- New York University Abu Dhabi (AE)
- Broad Institute (US)
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States
- Corresponding author
- Pelkey, Kenneth A
- McBain, Chris J
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2020-02-13
- Volume
- 9
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC7039679
- OpenAlex
- W3006461815
- Cited by
- 46
- References
- 95
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 6 · 2023: 4 · 2022: 7 · 2021: 6 · 2020: 5 · 2019: 1
- FWCI
- 2.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (Intramural research program)
- National Institute of Neurological Disorders and Stroke (NS081297, NS074972)
- National Institute of Mental Health (MH071679)
- National Institutes of Health (R01-MH111529, UG3MH120096)
- Simons Foundation
- Friends of FACES Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Keywords
- glutamic acid decarboxylase, VGLUT3, cholecystokinin, GABAergic interneurons, Dale's principle, network hyperexcitability, basket cells, glutamatergic signaling, schizophrenia, vitamin B6 deficiency
- MeSH terms
- Animals, gamma-Aminobutyric Acid, Interneurons, Glutamic Acid, Vesicular Glutamate Transport Proteins, Mice
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