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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.

Daily rhythms of physiology and behaviour are precisely timed by an endogenous circadian clock1,2. These include separate bouts of morning and evening activity, characteristic of Drosophila melanogaster and many other taxa, including mammals3,4,5. Whereas multiple oscillators have long been proposed to orchestrate such complex behavioural programmes6, their nature and interplay have remained elusive. By using cell-specific ablation, we show that the timing of morning and evening activity in Drosophila derives from two distinct groups of circadian neurons: morning activity from the ventral lateral neurons that express the neuropeptide PDF, and evening activity from another group of cells, including the dorsal lateral neurons. Although the two oscillators can function autonomously, cell-specific rescue experiments with circadian clock mutants indicate that they are functionally coupled.

The daily sleep cycle in humans and other mammals is driven by a complex circuit within which GABAergic sleep-promoting neurons oppose arousal systems. The latter includes the circadian system, aminergic/cholinergic systems as well as neurons secreting the peptide orexin/hypocretin, which contribute to sharp behavioral transitions (Lu and Greco, 2006). Drosophila sleep has recently been shown also to be controlled by GABAergic inputs, which act on unknown cells expressing the Rdl GABAA receptor (Agosto et al., 2008). We identify here the relevant Rdl-containing cells as a subset of the well-studied Drosophila circadian clock neurons, the PDF-expressing small and large ventral lateral neurons (LNvs). LNv activity regulates the total amount of sleep as well as the rate of sleep onset, and both large and small LNvs are part of the sleep circuit. Flies mutant for either the pdf gene or its receptor are hypersomnolent, and PDF acts on the LNvs themselves to control sleep. These features of the Drosophila sleep circuit, GABAergic control of sleep onset and maintenance as well as peptidergic control of arousal, support the idea that features of sleep circuit architecture as well as the mechanisms governing the behavioral transitions between sleep and wake are conserved between mammals and insects.