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

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

10.7554/elife.15271.016 ◽

2016 ◽

Cited By ~ 1

Author(s):

Andrew Lutas ◽

Carolina Lahmann ◽

Magali Soumillon ◽

Gary Yellen

Keyword(s):

Substantia Nigra ◽

Author Response ◽

Substantia Nigra Pars Reticulata ◽

Tonic Firing ◽

Leak Channel

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Acute dopamine receptor blockade in substantia nigra pars reticulata: a possible model for drug-induced Parkinsonism

Journal of Neurophysiology ◽

10.1152/jn.00579.2018 ◽

2018 ◽

Vol 120 (6) ◽

pp. 2922-2938 ◽

Cited By ~ 2

Author(s):

Verónica Alejandra Cáceres-Chávez ◽

Ricardo Hernández-Martínez ◽

Jesús Pérez-Ortega ◽

Marco Arieli Herrera-Valdez ◽

Jose J. Aceves ◽

...

Keyword(s):

Substantia Nigra ◽

Substantia Nigra Pars Reticulata ◽

Receptor Blockade ◽

Drug Induced ◽

Tonic Firing ◽

Neuron Firing ◽

Similar Preparation ◽

6 Hydroxydopamine ◽

Irregular Firing

Dopamine (DA) depletion modifies the firing pattern of neurons in the substantia nigra pars reticulata (SNr), shifting their mostly tonic firing toward irregularity and bursting, traits of pathological firing underlying rigidity and postural instability in Parkinson’s disease (PD) patients and animal models of Parkinsonism (PS). Drug-induced Parkinsonism (DIP) represents 20–40% of clinical cases of PS, becoming a problem for differential diagnosis, and is still not well studied with physiological tools. It may co-occur with tardive dyskinesia. Here we use in vitro slice preparations including the SNr to observe drug-induced pathological firing by using drugs that most likely produce it, DA-receptor antagonists (SCH23390 plus sulpiride), to compare with firing patterns found in DA-depleted tissue. The hypothesis is that SNr firing would be similar under both conditions, a prerequisite to the proposal of a similar preparation to test other DIP-producing drugs. Firing was analyzed with three complementary metrics, showing similarities between DA depletion and acute DA-receptor blockade. Moreover, blockade of either nonselective cationic channels or Cav3 T-type calcium channels hyperpolarized the membrane and abolished bursting and irregular firing, silencing SNr neurons in both conditions. Therefore, currents generating firing in control conditions are in part responsible for pathological firing. Haloperidol, a DIP-producing drug, reproduced DA-receptor antagonist firing modifications. Since acute DA-receptor blockade induces SNr neuron firing similar to that found in the 6-hydroxydopamine model of PS, output basal ganglia neurons may play a role in generating DIP. Therefore, this study opens the way to test other DIP-producing drugs. NEW & NOTEWORTHY Dopamine (DA) depletion enhances substantia nigra pars reticulata (SNr) neuron bursting and irregular firing, hallmarks of Parkinsonism. Several drugs, including antipsychotics, antidepressants, and calcium channel antagonists, among others, produce drug-induced Parkinsonism. Here we show the first comparison between SNr neuron firing after DA depletion vs. firing found after acute blockade of DA receptors. It was found that firing in both conditions is similar, implying that pathological SNr neuron firing is also a physiological correlate of drug-induced Parkinsonism.

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