1. Neuroscience
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Cortical ChAT+ neurons co-transmit acetylcholine and GABA in a target-and brain-region specific manner

  1. Adam J Granger
  2. Wengang Wang
  3. Keiramarie Robertson
  4. Mahmoud El-Rifai
  5. Andrea F Zanello
  6. Karina Bistrong
  7. Arpiar Saunders
  8. Brian W Chow
  9. Vicente Nuñez
  10. Miguel Turrero García
  11. Corey C Harwell
  12. Chenghua Gu
  13. Bernardo L Sabatini  Is a corresponding author
  1. Howard Hughes Medical Institute, Harvard Medical School, United States
  2. Harvard Medical School, United States
Research Article
  • Cited 3
  • Views 2,617
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Cite this article as: eLife 2020;9:e57749 doi: 10.7554/eLife.57749

Abstract

The mouse cerebral cortex contains neurons that express choline acetyltransferase (ChAT) and are a potential local source of acetylcholine. However, the neurotransmitters released by cortical ChAT+ neurons and their synaptic connectivity are unknown. We show that the nearly all cortical ChAT+ neurons in mice are specialized VIP+ interneurons that release GABA strongly onto other inhibitory interneurons and acetylcholine sparsely onto layer 1 interneurons and other VIP+/ChAT+ interneurons. This differential transmission of ACh and GABA based on the postsynaptic target neuron is reflected in VIP+/ChAT+ interneuron pre-synaptic terminals, as quantitative molecular analysis shows that only a subset of these are specialized to release acetylcholine. In addition, we identify a separate, sparse population of non-VIP ChAT+ neurons in the medial prefrontal cortex with a distinct developmental origin that robustly release acetylcholine in layer 1. These results demonstrate both cortex-region heterogeneity in cortical ChAT+ interneurons and target-specific co-release of acetylcholine and GABA.

Article and author information

Author details

  1. Adam J Granger

    Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wengang Wang

    Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Keiramarie Robertson

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Mahmoud El-Rifai

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Andrea F Zanello

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Karina Bistrong

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Arpiar Saunders

    Department of Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Brian W Chow

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Vicente Nuñez

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Miguel Turrero García

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7294-169X
  11. Corey C Harwell

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Chenghua Gu

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4212-7232
  13. Bernardo L Sabatini

    Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    For correspondence
    bsabatini@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0095-9177

Funding

National Institute of Neurological Disorders and Stroke (R37 NS046579)

  • Bernardo L Sabatini

National Institute of Neurological Disorders and Stroke (K99 NS102429)

  • Adam J Granger

National Institute of Neurological Disorders and Stroke (P30Ns072030)

  • Mahmoud El-Rifai

Jane Coffin Childs Memorial Fund for Medical Research

  • Adam J Granger

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the NIH, and according to strict adherence to the protocols approved by the Institutional Animal Care and Use Committee (IACUC) of Harvard Medical School (protocol #IS00000571). Routine examination, veterinary care, disease surveillance, and animal use compliance were all carried out by certified veterinary staff of the Harvard Center for Comparative Medicine (HCCM) in addition to full daily animal husbandry provided by trained animal technicians.

Reviewing Editor

  1. Solange P Brown, Johns Hopkins University, United States

Publication history

  1. Received: April 10, 2020
  2. Accepted: July 1, 2020
  3. Accepted Manuscript published: July 2, 2020 (version 1)
  4. Version of Record published: July 14, 2020 (version 2)

Copyright

© 2020, Granger et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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