Cited by 46Neuroscience and Neuropharmacology ResearchNeural dynamics and brain functionEpilepsy research and treatment

Paradoxical network excitation by glutamate release from VGluT3+ GABAergic interneurons

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Pelkey, Kenneth A, Calvigioni, Daniela, Fang, Calvin, Vargish, Geoffrey, Ekins, Tyler, Auville, Kurt, Wester, Jason C, Lai, Mandy +9 more·2020·eLife

Abstract

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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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
Venue
eLife
Published
2020-02-13
Volume
9
ISSN
2050-084X (ISSN-L)
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
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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