Editors' ChoiceNeuroscience

Awake, but not hyperactive

Sci. Signal.  14 Jul 2015:
Vol. 8, Issue 385, pp. ec189
DOI: 10.1126/scisignal.aac9968

Neurons from the tuberomammilary nucleus (TMN) project throughout the brain to control wakefulness and signal through a nonsynaptic mechanism called volume release, which activates extrasynaptic receptors, instead of through synaptic transmission. These neurons synthesize and release histamine from varicosities along the axons. These neurons also contain γ-amino butyric acid (GABA), and Yu et al. found that they also contain the transporter vgat, which is necessary to import GABA into vesicles for release, suggesting that histaminergic TMN neurons cotransmit histaminergic and GABAergic signals. To demonstrate that GABA release by the TMN was functionally important, the authors generated mice in which vgat was knocked down or genetically depleted in TMN neurons. These vgat-deficient mice were hyperactive, moving greater distances and moving faster than did control animals. The vgat-deficient mice also slept less and maintained a hyperactive state after sleep deprivation. Optogenetic activation of TMN neurons in slice preparations from mice engineered to express channel rhodopsin in the histaminergic TMN neurons in the context of the control mice or the vgat-deficient mice showed that stimulation of these neurons produced a slowly developing increase in the holding current, consistent with that of tonic activation of extrasynaptic ionotropic GABA receptors, and that this current was absent in preparations from the vgat-deficient mice. The tonic GABA current was present when interneuron activity or histamine receptors were blocked pharmacologically, indicating a direct effect of released GABA rather than an effect mediated by altered neural circuit activity. The presence of a GABAA receptor antagonist blocked the tonic GABA current. Optogenetic stimulation increased the frequency of spontaneous postsynaptic currents in the neocortex in a manner dependent on histamine receptors, but independent of vgat. Thus, wakefulness is controlled by neurons that release both an excitatory signal (histamine) and an inhibitory signal (GABA) to maintain the appropriate state of arousal and sleep-wake balance.

X. Yu, Z. Ye, C. M. Houston, A. Y. Zecharia, Y. Ma, Z. Zhang, D. S. Uygun, S. Parker, A. L. Vyssotski, R. Yustos, N. P. Franks, S. G. Brickley, W. Wisden, Wakefulness is governed by GABA and histamine cotransmission. Neuron 87, 164–178 (2015). [PubMed]