Paradoxical network excitation by glutamate release from VGluT3+ GABAergic interneurons

  1. Kenneth A Pelkey  Is a corresponding author
  2. Daniela Calvigioni
  3. Calvin Fang
  4. Geoffrey Vargish
  5. Tyler Ekins
  6. Kurt Auville
  7. Jason C Wester
  8. Mandy Lai
  9. Connie Mackenzie-Gray Scott
  10. Xiaoqing Yuan
  11. Steven Hunt
  12. Daniel Abebe
  13. Qing Xu
  14. Jordane Dimidschstein
  15. Gordon Fishell
  16. Ramesh Chittajallu
  17. Chris J McBain  Is a corresponding author
  1. NICHD/NIH, United States
  2. New York University Abu Dhabi, United Arab Emirates
  3. Broad Institute of MIT and Harvard, United States
  4. 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.

Article and author information

Author details

  1. Kenneth A Pelkey

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    For correspondence
    pelkeyk2@mail.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9731-1336
  2. Daniela Calvigioni

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Calvin Fang

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Geoffrey Vargish

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Tyler Ekins

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kurt Auville

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jason C Wester

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Mandy Lai

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Connie Mackenzie-Gray Scott

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Xiaoqing Yuan

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Steven Hunt

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Daniel Abebe

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Qing Xu

    Center for Genomics and Systems Biology, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
    Competing interests
    The authors declare that no competing interests exist.
  14. Jordane Dimidschstein

    Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Gordon Fishell

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Ramesh Chittajallu

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Chris J McBain

    Section on Cellular and Synaptic Physiology, NICHD/NIH, Bethesda, United States
    For correspondence
    mcbainc@mail.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5909-0157

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).

Reviewing Editor

  1. Marlene Bartos, University of Freiburg, Germany

Publication history

  1. Received: September 19, 2019
  2. Accepted: February 12, 2020
  3. Accepted Manuscript published: February 13, 2020 (version 1)
  4. Version of Record published: February 24, 2020 (version 2)

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.

Metrics

  • 3,173
    Page views
  • 555
    Downloads
  • 14
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Kenneth A Pelkey
  2. Daniela Calvigioni
  3. Calvin Fang
  4. Geoffrey Vargish
  5. Tyler Ekins
  6. Kurt Auville
  7. Jason C Wester
  8. Mandy Lai
  9. Connie Mackenzie-Gray Scott
  10. Xiaoqing Yuan
  11. Steven Hunt
  12. Daniel Abebe
  13. Qing Xu
  14. Jordane Dimidschstein
  15. Gordon Fishell
  16. Ramesh Chittajallu
  17. Chris J McBain
(2020)
Paradoxical network excitation by glutamate release from VGluT3+ GABAergic interneurons
eLife 9:e51996.
https://doi.org/10.7554/eLife.51996
  1. Further reading

Further reading

    1. Neuroscience
    Maria Cecilia Martinez, Camila Lidia Zold ... Mariano Andrés Belluscio
    Research Article

    The automatic initiation of actions can be highly functional. But occasionally these actions cannot be withheld and are released at inappropriate times, impulsively. Striatal activity has been shown to participate in the timing of action sequence initiation and it has been linked to impulsivity. Using a self-initiated task, we trained adult male rats to withhold a rewarded action sequence until a waiting time interval has elapsed. By analyzing neuronal activity we show that the striatal response preceding the initiation of the learned sequence is strongly modulated by the time subjects wait before eliciting the sequence. Interestingly, the modulation is steeper in adolescent rats, which show a strong prevalence of impulsive responses compared to adults. We hypothesize this anticipatory striatal activity reflects the animals’ subjective reward expectation, based on the elapsed waiting time, while the steeper waiting modulation in adolescence reflects age-related differences in temporal discounting, internal urgency states, or explore–exploit balance.

    1. Computational and Systems Biology
    2. Neuroscience
    Sergio Oscar Verduzco-Flores, Erik De Schutter
    Research Article Updated

    How dynamic interactions between nervous system regions in mammals performs online motor control remains an unsolved problem. In this paper, we show that feedback control is a simple, yet powerful way to understand the neural dynamics of sensorimotor control. We make our case using a minimal model comprising spinal cord, sensory and motor cortex, coupled by long connections that are plastic. It succeeds in learning how to perform reaching movements of a planar arm with 6 muscles in several directions from scratch. The model satisfies biological plausibility constraints, like neural implementation, transmission delays, local synaptic learning and continuous online learning. Using differential Hebbian plasticity the model can go from motor babbling to reaching arbitrary targets in less than 10 min of in silico time. Moreover, independently of the learning mechanism, properly configured feedback control has many emergent properties: neural populations in motor cortex show directional tuning and oscillatory dynamics, the spinal cord creates convergent force fields that add linearly, and movements are ataxic (as in a motor system without a cerebellum).