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
Share this article
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
  2. Download BibTeX
  3. Download .RIS

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.

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

  • 3,372
    views
  • 503
    downloads
  • 36
    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. 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

Categories and tags

Research organism

Further reading

    1. Cell Biology

    Stratification of enterochromaffin cells by single-cell expression analysis

    Yan Song, Linda J Fothergill ... Gene W Yeo
    Research Article

    Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify 14 EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic, and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.

    1. Cell Biology

    Small-molecule activation of TFEB alleviates Niemann–Pick disease type C via promoting lysosomal exocytosis and biogenesis

    Kaili Du, Hongyu Chen ... Dan Li
    Research Article

    Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

    1. Cell Biology
    2. Developmental Biology

    Lens Development: Bringing signaling complexity into focus

    Sarah Y Coomson, Salil A Lachke
    Insight

    A study in mice reveals key interactions between proteins involved in fibroblast growth factor signaling and how they contribute to distinct stages of eye lens development.