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

Abstract
Article and author information
Metrics

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.

Article and author information

Author details

Andrew Lutas

Department of Neurobiology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Carolina Lahmann

Department of Neurobiology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Magali Soumillon

Broad Institute, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
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).

Copyright

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.