title: Metabolism regulates the spontaneous firing of substantia nigra pars reticulata neurons via KATP and nonselective cation channels.
abstract: Neurons use glucose to fuel glycolysis and provide substrates for mitochondrial respiration, but neurons can also use alternative fuels that bypass glycolysis and feed directly into mitochondria. To determine whether neuronal pacemaking depends on active glucose metabolism, we switched the metabolic fuel from glucose to alternative fuels, lactate or β-hydroxybutyrate, while monitoring the spontaneous firing of GABAergic neurons in mouse substantia nigra pars reticulata (SNr) brain slices. We found that alternative fuels, in the absence of glucose, sustained SNr spontaneous firing at basal rates, but glycolysis may still be supported by glycogen in the absence of glucose. To prevent any glycogen-fueled glycolysis, we directly inhibited glycolysis using either 2-deoxyglucose or iodoacetic acid. Inhibiting glycolysis in the presence of alternative fuels lowered SNr firing to a slower sustained firing rate. Surprisingly, we found that the decrease in SNr firing was not mediated by ATP-sensitive potassium (KATP) channel activity, but if we lowered the perfusion flow rate or omitted the alternative fuel, KATP channels were activated and could silence SNr firing. The KATP-independent slowing of SNr firing that occurred with glycolytic inhibition in the presence of alternative fuels was consistent with a decrease in a nonselective cationic conductance. Although mitochondrial metabolism alone can prevent severe energy deprivation and KATP channel activation in SNr neurons, active glucose metabolism appears important for keeping open a class of ion channels that is crucial for the high spontaneous firing rate of SNr neurons.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Andrew
authors.identifier: http://orcid.org/0000-0002-6991-2898
authors.initials: A
authors.lastname: Lutas
authors.affiliation: Laboratory of Neurobiology, National Institute of Environmental Research, National Institutes of Health, Research Triangle Park, North Carolina 27709.
authors.forename: Lutz
authors.identifier: http://orcid.org/0000-0002-0775-8661
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and gary_yellen@hms.harvard.edu.
authors.forename: Gary
authors.identifier: http://orcid.org/0000-0003-4228-7866
authors.initials: G
authors.lastname: Yellen
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D003847:Deoxyglucose / Q000494:pharmacology; D005260:Female; D059330:GABAergic Neurons / Q000502:physiology*; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D019807:Iodoacetic Acid / Q000494:pharmacology; D054086:KATP Channels / Q000502:physiology*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D065841:Pars Reticulata / Q000166:cytology* / Q000502:physiology*; D050051:Transient Receptor Potential Channels / Q000502:physiology*
chemical_list: D054086:KATP Channels; D050051:Transient Receptor Potential Channels; D019344:Lactic Acid; D003847:Deoxyglucose; D020155:3-Hydroxybutyric Acid; D019807:Iodoacetic Acid
keywords: KATP; Trp channel; excitability; glycolysis