The Leak Channel NALCN Controls Tonic Firing and Glycolytic Sensitivity of Substantia Nigra Pars Reticulata Neurons

Elife. 2016 May 13;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.

Keywords: basal ganglia; leak current; metabolism and excitability; mouse; neuroscience; spontaneous firing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials*
  • Animals
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / physiology*
  • Gene Expression Profiling
  • Glycolysis*
  • Ion Channels / metabolism*
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Pars Reticulata / physiology*
  • Sequence Analysis, RNA
  • Single-Cell Analysis

Substances

  • Ion Channels
  • NALCN protein, mouse
  • Nerve Tissue Proteins