1. Cell Biology
  2. Neuroscience

Cell-type specific regulation of neuronal intrinsic excitability by macroautophagy

  1. Ori J Lieberman  Is a corresponding author
  2. Micah D Frier
  3. Avery F McGuirt
  4. Christopher J Griffey
  5. Elizabeth Rafikian
  6. Mu Yang
  7. Ai Yamamoto
  8. Anders Borgkvist
  9. Emanuela Santini
  10. David Sulzer  Is a corresponding author
  1. Columbia University, United States
  2. Karolinska Institute, Sweden
https://doi.org/10.7554/eLife.50843
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Cite this article
  1. Ori J Lieberman
  2. Micah D Frier
  3. Avery F McGuirt
  4. Christopher J Griffey
  5. Elizabeth Rafikian
  6. Mu Yang
  7. Ai Yamamoto
  8. Anders Borgkvist
  9. Emanuela Santini
  10. David Sulzer
(2020)
Cell-type specific regulation of neuronal intrinsic excitability by macroautophagy
eLife 9:e50843.
https://doi.org/10.7554/eLife.50843
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Abstract

The basal ganglia are a group of subcortical nuclei that contribute to action selection and reinforcement learning. The principal neurons of the striatum, spiny projection neurons of the direct (dSPN) and indirect (iSPN) pathways, maintain low intrinsic excitability, requiring convergent excitatory inputs to fire. Here, we examined the role of autophagy in mouse SPN physiology and animal behavior by generating conditional knockouts of Atg7 in either dSPNs or iSPNs. Loss of autophagy in either SPN population led to changes in motor learning but distinct effects on cellular physiology. dSPNs, but not iSPNs, required autophagy for normal dendritic structure and synaptic input. In contrast, iSPNs, but not dSPNs, were intrinsically hyperexcitable due to reduced function of the inwardly rectifying potassium channel, Kir2. These findings define a novel mechanism by which autophagy regulates neuronal activity: control of intrinsic excitability via the regulation of potassium channel function.

Data availability

All relevant data are present within the manuscript and supporting files. Source data files have been provided for all Figures.

Article and author information

Author details

  1. Ori J Lieberman

    Department of Psychiatry, Columbia University, New York, United States
    For correspondence
    ojl2106@columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0467-0875

  2. Micah D Frier

    Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Avery F McGuirt

    Department of Psychiatry, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Christopher J Griffey

    Department of Neurology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Elizabeth Rafikian

    Institute for Genomic Medicine, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Mu Yang

    Institute for Genomic Medicine, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Ai Yamamoto

    Department of Neurology, Columbia 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:" 0000-0002-7059-2449

  8. Anders Borgkvist

    Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  9. Emanuela Santini

    Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  10. David Sulzer

    Department of Psychiatry, Columbia University, New York, United States
    For correspondence
    ds43@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7632-0439

Funding

National Institute of Mental Health (5F30MH114390-02)

  • Ori J Lieberman

National Institute of General Medical Sciences (T32GM007367)

  • Ori J Lieberman
  • Christopher J Griffey

National Institute on Drug Abuse (R01DA007418)

  • David Sulzer

Simons Foundation (514813)

  • David Sulzer

JPB Foundation

  • David Sulzer

National Institute of Neurological Disorders and Stroke (R00NS087112)

  • Emanuela Santini

National Institute of Neurological Disorders and Stroke (R01NS063973)

  • Ai Yamamoto

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

Reviewing Editor

  1. Andrew B West, Duke University, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (AAAV9459 and AAAR4414) of Columbia University.

Version history

  1. Received: August 4, 2019
  2. Accepted: January 7, 2020
  3. Accepted Manuscript published: January 8, 2020 (version 1)
  4. Version of Record published: January 27, 2020 (version 2)

Copyright

© 2020, Lieberman 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. Ori J Lieberman
  2. Micah D Frier
  3. Avery F McGuirt
  4. Christopher J Griffey
  5. Elizabeth Rafikian
  6. Mu Yang
  7. Ai Yamamoto
  8. Anders Borgkvist
  9. Emanuela Santini
  10. David Sulzer
(2020)
Cell-type specific regulation of neuronal intrinsic excitability by macroautophagy
eLife 9:e50843.
https://doi.org/10.7554/eLife.50843

Share this article

https://doi.org/10.7554/eLife.50843

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