Wakefulness Is Governed by GABA and Histamine Cotransmission

Summary

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) GABA _A 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.

Highlights

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  Histaminergic axons corelease GABA into the neocortex and striatum

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  The released GABA produces slow tonic inhibition

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  Reducing vgat expression in histaminergic neurons increases wakefulness

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  Histamine-GABA axons will coordinate tonic inhibition over large cortical areas

Abstract

Hypothalamic histamine neurons are well known as excitatory wake-promoting neurons. But they also contain GABA. In this paper, Yu et al. functionally demonstrate that histaminergic axons in the neocortex corelease a slow paracrine GABA signal to suppress wakefulness.