title: Wakefulness Is Governed by GABA and Histamine Cotransmission.
abstract: Histaminergic neurons in the tuberomammilary nucleus (TMN) of the hypothalamus form a widely projecting, wake-active network that sustains arousal. Yet most histaminergic neurons contain GABA. Selective siRNA knockdown of the vesicular GABA transporter (vgat, SLC32A1) in histaminergic neurons produced hyperactive mice with an exceptional amount of sustained wakefulness. Ablation of the vgat gene throughout the TMN further sharpened this phenotype. Optogenetic stimulation in the caudate-putamen and neocortex of "histaminergic" axonal projections from the TMN evoked tonic (extrasynaptic) GABAA receptor Cl(-) currents onto medium spiny neurons and pyramidal neurons. These currents were abolished following vgat gene removal from the TMN area. Thus wake-active histaminergic neurons generate a paracrine GABAergic signal that serves to provide a brake on overactivation from histamine, but could also increase the precision of neocortical processing. The long range of histamine-GABA axonal projections suggests that extrasynaptic inhibition will be coordinated over large neocortical and striatal areas.
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Catriona M
authors.initials: CM
authors.lastname: Houston
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Anna Y
authors.initials: AY
authors.lastname: Zecharia
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: David S
authors.initials: DS
authors.lastname: Uygun
authors.affiliation: Department of Physics, Imperial College London, London SW7 2AZ, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Parker
authors.affiliation: Institute of Neuroinformatics, University of Zürich/ETH Zürich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Alexei L
authors.initials: AL
authors.lastname: Vyssotski
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Raquel
authors.initials: R
authors.lastname: Yustos
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK; Centre for Neurotechnology, Imperial College London, London SW7 2AZ, UK. Electronic address: n.franks@imperial.ac.uk.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Franks
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK; Centre for Neurotechnology, Imperial College London, London SW7 2AZ, UK. Electronic address: s.brickley@imperial.ac.uk.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Brickley
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK; Centre for Neurotechnology, Imperial College London, London SW7 2AZ, UK. Electronic address: w.wisden@imperial.ac.uk.
authors.forename: William
authors.initials: W
authors.lastname: Wisden
mesh_terms: D000818:Animals; D001369:Axons; D055785:Gene Knockdown Techniques; D006632:Histamine / Q000378:metabolism*; D007026:Hypothalamic Area, Lateral / Q000378:metabolism*; D051379:Mice; D019579:Neocortex / Q000378:metabolism*; D017072:Neostriatum / Q000378:metabolism*; D009433:Neural Inhibition / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D062308:Optogenetics; D017966:Pyramidal Cells / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D009435:Synaptic Transmission; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics; D014851:Wakefulness / Q000235:genetics / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D011963:Receptors, GABA-A; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D005680:gamma-Aminobutyric Acid; D006632:Histamine