Cell Biology

Sleep Circuit

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Science  25 Apr 2014:
Vol. 344, Issue 6182, pp. 341
DOI: 10.1126/science.344.6182.341-b
CREDIT: DIGITALSKILLET/ISTOCKPHOTO

The neurotransmitter molecule γ-aminobutyric acid (GABA) promotes sleep in mammals and flies, but the molecular details of this regulation have not been clear. Chen et al. provide new insight into this complex pathway, finding that GABA transaminase (GABAT), a mitochondrial enzyme that breaks down GABA, controls GABA amounts to affect sleep in Drosophila. Sleep is controlled by the protein sleepless (SSS), which is expressed in neurons of the fly brain. Its absence in mutant flies increases neural activity and decreases sleep. Mutant flies lacking SSS expressed more GABAT in the brain. Consequently, GABA amounts decreased by 30% in the brain, and compared to control flies, mutant flies slept less. Disrupting GABAT expression increased GABA amounts and boosted total daily sleep. Furthermore, reducing GABAT in mutant flies lacking SSS restored sleep. Flies expressing mutant GABAT showed an increase in overall daily sleep, and the time it took flies to fall asleep was reduced. Moreover, treatment of adult flies lacking SSS with ethanolamine O-sulfate, an inhibitor of GABAT, rescued sleep. These results suggest that SSS promotes sleep and that its absence increases neuron excitability, which may demand more energy. This could alter cell metabolism in neighboring glia, including changes in GABAT activity in the mitochondria. Changes in GABAT activity have been implicated in epilepsy (characterized by increased neural activity) and other neuropsychiatric disorders. The connection of GABAT and cell metabolism to sleep control may explain sleep problems associated with these conditions.

Mol. Psychiatry 10.1038/mp.2014.11 (2014).

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