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).

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

  • 4,013
    views
  • 635
    downloads
  • 39
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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

Share this article

https://doi.org/10.7554/eLife.51996

Further reading

    1. Neuroscience
    Zhujun Shao, Mengya Zhang, Qing Yu
    Research Article

    When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.

    1. Neuroscience
    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.