Id2 GABAergic interneurons comprise a neglected fourth major group of cortical inhibitory cells

  1. Robert Machold
  2. Shlomo Dellal
  3. Manuel Valero
  4. Hector Zurita
  5. Illya Kruglikov
  6. John Hongyu Meng
  7. Jessica L Hanson
  8. Yoshiko Hashikawa
  9. Benjamin Schuman
  10. György Buzsáki
  11. Bernardo Rudy  Is a corresponding author
  1. New York University, United States
  2. Hospital del Mar Medical Research Institute (IMIM), Spain
  3. University of Colorado Boulder, United States

Abstract

Cortical GABAergic interneurons (INs) represent a diverse population of mainly locally projecting cells that provide specialized forms of inhibition to pyramidal neurons and other INs. Most recent work on INs has focused on subtypes distinguished by expression of Parvalbumin (PV), Somatostatin (SST), or Vasoactive Intestinal Peptide (VIP). However, a fourth group that includes neurogliaform cells (NGFCs) has been less well characterized due to a lack of genetic tools. Here, we show that these INs can be accessed experimentally using intersectional genetics with the gene Id2. We find that outside of layer 1 (L1), the majority of Id2 INs are NGFCs that express high levels of neuropeptide Y (NPY) and exhibit a late-spiking firing pattern, with extensive local connectivity. While much sparser, non-NGFC Id2 INs had more variable properties, with most cells corresponding to a diverse group of INs that strongly expresses the neuropeptide CCK. In vivo, using silicon probe recordings, we observed several distinguishing aspects of NGFC activity, including a strong rebound in activity immediately following the cortical down state during NREM sleep. Our study provides insights into IN diversity and NGFC distribution and properties, and outlines an intersectional genetics approach for further study of this underappreciated group of INs.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files; Source Data files have been provided for Figures 1, 2, 4, Table 1, Figure 1 - figure supplement 1 and Figure 1 - figure supplement 2.

The following previously published data sets were used
    1. Yao et al.
    (2021) Whole Cortex and Hippocampus - 10x genomics (2020) with 10x-Smart-Seq Taxonomy
    https://portal.brain-map.org/atlases-and-data/rnaseq/mouse-whole-cortex-and-hippocampus-10x.

Article and author information

Author details

  1. Robert Machold

    Neuroscience Institute, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6261-496X
  2. Shlomo Dellal

    Neuroscience Institute, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Manuel Valero

    Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Hector Zurita

    Neuroscience Institute, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Illya Kruglikov

    Neuroscience Institute, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. John Hongyu Meng

    Neuroscience Institute, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jessica L Hanson

    Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Yoshiko Hashikawa

    Neuroscience Institute, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Benjamin Schuman

    Neuroscience Institute, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. György Buzsáki

    Neuroscience Institute, Langone Medical Center, Department of Neurology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3100-4800
  11. Bernardo Rudy

    Neuroscience Institute, New York University, New York, United States
    For correspondence
    Bernardo.Rudy@nyulangone.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1367-7136

Funding

National Institutes of Health (P01NS074972)

  • Bernardo Rudy

National Institutes of Health (R01NS110079)

  • Bernardo Rudy

National Institutes of Health (U19NS107616)

  • György Buzsáki

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 experimental animals were handled with care to minimize suffering in accordance with institutional animal care and use committee (IACUC) protocols approved by the Division of Comparative Medicine at the NYU Langone Medical Center for Dr. Bernardo Rudy's lab (#IA15-01465 and #IA15-01473).

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

Version history

  1. Received: December 30, 2022
  2. Accepted: August 21, 2023
  3. Accepted Manuscript published: September 4, 2023 (version 1)

Copyright

© 2023, Machold 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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  1. Robert Machold
  2. Shlomo Dellal
  3. Manuel Valero
  4. Hector Zurita
  5. Illya Kruglikov
  6. John Hongyu Meng
  7. Jessica L Hanson
  8. Yoshiko Hashikawa
  9. Benjamin Schuman
  10. György Buzsáki
  11. Bernardo Rudy
(2023)
Id2 GABAergic interneurons comprise a neglected fourth major group of cortical inhibitory cells
eLife 12:e85893.
https://doi.org/10.7554/eLife.85893

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