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Modulation of GABAA receptor desensitization uncouples sleep onset and maintenance in Drosophila

2008; Nature Portfolio; Volume: 11; Issue: 3 Linguagem: Inglês

10.1038/nn2046

1546-1726

José L. Agosto, James C. Choi, Katherine M. Parisky, Geoffrey E. Stilwell, Michael Rosbash, Leslie C. Griffith,

Plant and animal studies

Many lines of evidence indicate that GABA and GABA(A) receptors make important contributions to human sleep regulation. Pharmacological manipulation of these receptors has differential effects on sleep onset and sleep maintenance insomnia. Here we show that sleep is regulated by GABA in Drosophila and that a mutant GABA(A) receptor, Rdl(A302S), specifically decreases sleep latency. The drug carbamazepine (CBZ) has the opposite effect on sleep; it increases sleep latency as well as decreasing sleep. Behavioral and physiological experiments indicated that Rdl(A302S) mutant flies are resistant to the effects of CBZ on sleep latency and that mutant RDL(A302S) channels are resistant to the effects of CBZ on desensitization, respectively. These results suggest that this biophysical property of the channel, specifically channel desensitization, underlies the regulation of sleep latency in flies. These experiments uncouple the regulation of sleep latency from that of sleep duration and suggest that the kinetics of GABA(A) receptor signaling dictate sleep latency.