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.
Highlights
Some neurons are capable of continuously firing action potentials in the complete absence of synaptic input (Hausser et al, 2004)
A tetrodotoxin-insensitive, tonic depolarizing current is necessary for spontaneous firing of substantia nigra pars reticulata (SNr) neurons, and this current has been attributed to constitutive activity of a nonselective cation channel (NSCC) (Atherton and Bevan, 2005; Zhou et al, 2008)
We tested the involvement of TRPM2, another NSCC we found to be expressed by SNr neurons
Summary
Some neurons are capable of continuously firing action potentials in the complete absence of synaptic input (Hausser et al, 2004). Electrophysiological studies of spontaneously active neurons have frequently reported the presence of a tonic current that maintains these neurons at a more depolarized membrane potential and likely allows them to continuously fire action potentials (Atherton and Bevan, 2005; Raman et al, 2000; Jackson et al, 2004; Taddese and Bean, 2002; Khaliq and Bean, 2010). This current, often referred to as a ’leak’ or ’background’ current, has characteristics of a nonselective cation current – it is sodium-dependent and has a reversal potential close to 0 mV.
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