Paradoxical network excitation by glutamate release from VGluT3+ GABAergic interneurons

Kenneth A. Pelkey, Daniela Calvigioni, Calvin Fang, Geoffrey Vargish, Tyler Ekins, Kurt Auville, Jason C. Wester, Mandy Lai, Connie Mackenzie Gray Scott, Xiaoqing Yuan, Steven Hunt, Daniel Abebe, Qing Xu, Jordane Dimidschstein, Gordon Fishell, Ramesh Chittajallu, Chris J. McBain

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere51996
StatePublished - Feb 2020

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology


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