Cell-type specific regulation of neuronal intrinsic excitability by macroautophagy
- Columbia University, United States
- Karolinska Institute, Sweden
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
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
- Andrew B West, Duke University, United States
Publication history
- Received: August 4, 2019
- Accepted: January 7, 2020
- Accepted Manuscript published: January 8, 2020 (version 1)
- 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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Cell-type specific regulation of neuronal intrinsic excitability by macroautophagy
eLife 9:e50843.
https://doi.org/10.7554/eLife.50843
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