title: Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but does not abolish glucose or pH responses of orexin/hypocretin neurons.
abstract: The firing of hypothalamic hypocretin/orexin neurons is vital for normal sleep-wake transitions, but its molecular determinants are not well understood. It was recently proposed that TASK (TWIK-related acid-sensitive potassium) channels [TASK1 (K(2P)3.1) and/or TASK3 (K(2P)9.1)] regulate neuronal firing and may contribute to the specialized responses of orexin neurons to glucose and pH. Here we tested these theories by performing patch-clamp recordings from orexin neurons directly identified by targeted green fluorescent protein labelling in brain slices from TASK1/3 double-knockout mice. The deletion of TASK1/3 channels significantly reduced the ability of orexin cells to generate high-frequency firing. Consistent with reduced excitability, individual action potentials from knockout cells had lower rates of rise, higher thresholds and more depolarized after-hyperpolarizations. However, orexin neurons from TASK1/3 knockout mice retained typical responses to glucose and pH, and the knockout animals showed normal food-anticipatory locomotor activity. Our results support a novel role for TASK genes in enhancing neuronal excitability and promoting high-frequency firing, but suggest that TASK1/3 subunits are not essential for orexin cell responses to glucose and pH.
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1 PD, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: González
authors.forename: Lise T
authors.initials: LT
authors.lastname: Jensen
authors.forename: Susan E
authors.initials: SE
authors.lastname: Doyle
authors.forename: Manuel
authors.initials: M
authors.lastname: Miranda-Anaya
authors.forename: Michael
authors.initials: M
authors.lastname: Menaker
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bayliss
authors.forename: Denis
authors.initials: D
authors.lastname: Burdakov
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000818:Animals; D001921:Brain / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D000068797:Orexins; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; C511784:TASK3 protein, mouse; D049452:Green Fluorescent Proteins; C420132:potassium channel subfamily K member 3; D005947:Glucose