A neuron–glia interaction involving GABA transaminase contributes to sleep loss in sleepless mutants

Abstract

Sleep is an essential process and yet mechanisms underlying it are not well understood. Loss of the Drosophila quiver/sleepless (qvr/sss) gene increases neuronal excitability and diminishes daily sleep, providing an excellent model for exploring the underpinnings of sleep regulation. Here, we used a proteomic approach to identify proteins altered in sss brains. We report that loss of sleepless post-transcriptionally elevates the CG7433 protein, a mitochondrial γ-aminobutyric acid transaminase (GABAT), and reduces GABA in fly brains. Loss of GABAT increases daily sleep and improves sleep consolidation, indicating that GABAT promotes wakefulness. Importantly, disruption of the GABAT gene completely suppresses the sleep phenotype of sss mutants, demonstrating that GABAT is required for loss of sleep in sss mutants. While SSS acts in distinct populations of neurons, GABAT acts in glia to reduce sleep in sss flies. Our results identify a novel mechanism of interaction between neurons and glia that is important for the regulation of sleep.

Day–night cycles and the sleep-promoting factor, Sleepless, affect stem cell activity in the Drosophila testis

“…GABA signaling is known to have a sleep-promoting role in both mammals and flies (29); sss P1 flies show reduced GABA levels, which when increased, largely restore sleep duration in these mutants (28). We found that increasing GABA signaling in sss P1 males slightly reduces GSC activity in the testis, although it does not restore the frequency of GSC divisions to the levels detected in WT flies (Fig.…”

“…We recently found that sss P1 flies show reduced levels of gamma-aminobutyric acid (GABA) in the brain, which are caused by increased levels of the enzyme that breaks down GABA: GABA transaminase (GABAT) (28). Interestingly, GABAergic signaling in the brain has previously been implicated in the regulation of sleep in both flies and mammals (29).…”

“…Interestingly, GABAergic signaling in the brain has previously been implicated in the regulation of sleep in both flies and mammals (29). Decreasing the activity of GABAT using a loss-of-function mutation in the gabat gene gabat PL00338 (gabat PL ) suppresses the sleep phenotype of sss mutants, indicating that GABAT is relevant for this phenotype (28). We sought to determine if the increase in GSCs division rates in sss P1 males was also attributable to changes in GABA signaling.…”

Independent Effects of γ-Aminobutyric Acid Transaminase (GABAT) on Metabolic and Sleep Homeostasis

“…5d). Previously, we observed that gabat f mutants have a sleep phenotype, sleeping on average a total of 100 -200 min more than wild-type controls (4). Because glutamate is one of the main wake-promoting neurotransmitters, we tested whether low glutamate also accounts for the sleep phenotype of gabat f .…”

“…We recently demonstrated that GABAT plays a role in sleep homeostasis in Drosophila (4). Specifically, fly strains with a null (gabat…”