title: The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons.
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.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Andrew
authors.identifier: 0000-0002-6991-2898
authors.initials: A
authors.lastname: Lutas
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Carolina
authors.initials: C
authors.lastname: Lahmann
authors.affiliation: Broad Institute, Cambridge, United States.
authors.forename: Magali
authors.initials: M
authors.lastname: Soumillon
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Gary
authors.identifier: 0000-0003-4228-7866
authors.initials: G
authors.lastname: Yellen
mesh_terms: D000200:Action Potentials; D000818:Animals; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D006019:Glycolysis; D007473:Ion Channels / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D065841:Pars Reticulata / Q000502:physiology*; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis
chemical_list: D007473:Ion Channels; D008565:Membrane Proteins; C519922:NALCN protein, mouse; D009419:Nerve Tissue Proteins
keywords: basal ganglia; leak current; metabolism and excitability; mouse; neuroscience; spontaneous firing