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The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons

  1. Andrew Lutas
  2. Carolina Lahmann
  3. Magali Soumillon
  4. Gary Yellen  Is a corresponding author
  1. Harvard Medical School, United States
  2. Broad Institute, United States
Research Article
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Cite this article as: eLife 2016;5:e15271 doi: 10.7554/eLife.15271

Abstract

Certain neuron types fire spontaneously at high rates, an ability that is crucial for their function in brain circuits. The spontaneously active GABAergic neurons of the substantia nigra pars reticulata (SNr), a major output of the basal ganglia, provide tonic inhibition of downstream brain areas. A depolarizing 'leak' current supports this firing pattern, but its molecular basis remains poorly understood. To understand how SNr neurons maintain tonic activity, we used single-cell RNA sequencing to determine the transcriptome of individual mouse SNr neurons. We discovered that SNr neurons express the sodium leak channel, NALCN, and that SNr neurons lacking NALCN have impaired spontaneous firing. In addition, NALCN is involved in the modulation of excitability by changes in glycolysis and by activation of muscarinic acetylcholine receptors. Our findings suggest that disruption of NALCN could impair the basal ganglia circuit, which may underlie the severe motor deficits in humans carrying mutations in NALCN.

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Author details

  1. Andrew Lutas

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Carolina Lahmann

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Magali Soumillon

    Broad Institute, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Gary Yellen

    Department of Neurobiology, Harvard Medical School, Boston, United States
    For correspondence
    gary_yellen@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

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 experimental manipulations were performed in accordance with protocols approved by the Harvard Medical Area Standing Committee on Animal Care (#03506).

Reviewing Editor

  1. Indira M Raman, Northwestern University, United States

Publication history

  1. Received: February 15, 2016
  2. Accepted: May 12, 2016
  3. Accepted Manuscript published: May 13, 2016 (version 1)
  4. Version of Record published: June 10, 2016 (version 2)

Copyright

© 2016, Lutas 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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