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Neuron. 2015 Jul 1;87(1):164-78. doi: 10.1016/j.neuron.2015.06.003. Epub 2015 Jun 18.

Wakefulness Is Governed by GABA and Histamine Cotransmission.

Author information

1
Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
2
Department of Physics, Imperial College London, London SW7 2AZ, UK.
3
Institute of Neuroinformatics, University of Zürich/ETH Zürich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
4
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.
5
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.
6
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.

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.

PMID:
26094607
PMCID:
PMC4509551
DOI:
10.1016/j.neuron.2015.06.003
[Indexed for MEDLINE]
Free PMC Article

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