Paradoxical network excitation by glutamate release from VGluT3+ GABAergic interneurons
- NICHD/NIH, United States
- New York University Abu Dhabi, United Arab Emirates
- Broad Institute of MIT and Harvard, United States
- Harvard Medical School, United States
Abstract
In violation of Dale's principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter 3 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.
Data availability
All data analyzed in this study are included in the manuscript/supporting files.
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Author details
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (Intramural research program)
- Chris J McBain
National Institute of Neurological Disorders and Stroke (NS081297; NS074972)
- Gordon Fishell
National Institute of Mental Health (MH071679)
- Gordon Fishell
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were conducted in accordance with animal protocols approved by the National Institutes of Health (ASP# 17-045).
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Paradoxical network excitation by glutamate release from VGluT3+ GABAergic interneurons
eLife 9:e51996.
https://doi.org/10.7554/eLife.51996
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