1. Cell Biology
  2. Neuroscience
Download icon

Cell-type specific regulation of neuronal intrinsic excitability by macroautophagy

Research Article
  • Cited 15
  • Views 2,396
  • Annotations
Cite this article as: eLife 2020;9:e50843 doi: 10.7554/eLife.50843

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.

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.

Reviewing Editor

  1. Andrew B West, Duke University, United States

Publication 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.

Metrics

  • 2,396
    Page views
  • 392
    Downloads
  • 15
    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)

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

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

Further reading

    1. Cell Biology
    Natalya Pashkova et al.
    Research Article

    Attachment of ubiquitin (Ub) to cell surface proteins serves as a signal for internalization via clathrin-mediated endocytosis (CME). How ubiquitinated membrane proteins engage the internalization apparatus remains unclear. The internalization apparatus contains proteins such as Epsin and Eps15, which bind Ub, potentially acting as adaptors for Ub-based internalization signals. Here we show that additional components of the endocytic machinery including CALM, HIP1R, and Sla2 bind Ub via their N-terminal ANTH domain, a domain belonging to the superfamily of ENTH and VHS domains. Structural studies revealed that Ub binds with µM affinity to a unique C-terminal region within the ANTH domain not found in ENTH domains. Functional studies showed that combined loss of Ub-binding by ANTH-domain proteins and other Ub-binding domains within the yeast internalization apparatus caused defects in the Ub-dependent internalization of the GPCR Ste2 that was engineered to rely exclusively on Ub as an internalization signal. In contrast, these mutations had no effect on the internalization of Ste2 engineered to use an alternate Ub-independent internalization signal. These studies define new components of the internalization machinery that work collectively with Epsin and Eps15 to specify recognition of Ub as an internalization signal.

    1. Cell Biology
    Richa Sardana et al.
    Short Report

    Protein glycosylation in the Golgi is a sequential process that requires proper distribution of transmembrane glycosyltransferase enzymes in the appropriate Golgi compartments. Some of the cytosolic machinery required for the steady-state localization of some Golgi enzymes are known but existing models do not explain how many of these enzymes are localized. Here, we uncover the role of an integral membrane protein in yeast, Erd1, as a key facilitator of Golgi glycosyltransferase recycling by directly interacting with both the Golgi enzymes and the cytosolic receptor, Vps74. Loss of Erd1 function results in mislocalization of Golgi enzymes to the vacuole/lysosome. We present evidence that Erd1 forms an integral part of the recycling machinery and ensures productive recycling of several early Golgi enzymes. Our work provides new insights on how the localization of Golgi glycosyltransferases is spatially and temporally regulated, and is finely tuned to the cues of Golgi maturation.