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Wakefulness Is Governed by GABA and Histamine Cotransmission


Yu, Xiao; Ye, Zhiwen; Houston, Catriona M; Zecharia, Anna Y; Ma, Ying; Zhang, Zhe; Uygun, David S; Parker, Susan; Vyssotski, Alexei L; Yustos, Raquel; Franks, Nicholas P; Brickley, Stephen G; Wisden, William (2015). Wakefulness Is Governed by GABA and Histamine Cotransmission. Neuron Glia Biology, 87(1):164-178.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Neuroinformatics
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2015
Deposited On:23 Feb 2016 10:55
Last Modified:13 Aug 2017 18:22
Publisher:Cambridge University Press
Series Name:Neuron
Number of Pages:15
ISSN:1740-925X
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.neuron.2015.06.003
Official URL:http://www.cell.com/neuron/abstract/S0896-6273%2815%2900516-4
PubMed ID:26094607

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