Furthermore, altering Cv-c function in adult FB neurons demonstrates the sleep

defect is not of developmental origin. Taken together, these data point directly to the FB neurons—and functioning Cv-c within these GS 1101 neurons—as critical for proper sleep homeostasis. To explore this idea further, Donlea et al. (2014) performed direct electrophysiological recordings of both wild-type and cv-c mutant FB neurons before, during, and after sleep deprivation. First, they found a critical role for Cv-c in maintaining electrical excitability of FB neurons under current-clamp recordings—most wild-type FB neurons were excited by depolarizing current, while most cv-c mutant neurons remained electrically silent with reduced input resistances (Rm) and membrane time constants (τm). Cv-c is not required in all neuron types, as olfactory

projection neurons remain electrically normal in cv-c mutants. Most intriguingly, they observed that wild-type FB neurons increased their electrical excitability in sleep-deprived flies and returned to baseline excitability following recovery sleep. This sleep deprivation-dependent modulation required functional Cv-c, as cv-c mutant FB neurons failed to alter electrical excitability to prolonged wakefulness. Only the scaffolding of a full sleep homeostasis model is brought into view by these results: some unknown direct or indirect signal for sleep pressure is transmitted into changes in electrical excitability of the major sleep output neurons, 3-mercaptopyruvate sulfurtransferase and this change depends, in Epigenetics Compound Library solubility dmso an unknown way, on Cv-c (Figure 1). However, the potential

implications of the model are substantial. In its strongest and perhaps most elegant form, the FB sleep output neurons themselves would act as a kind of sleep pressure antenna, directly receiving homeostatic cues and converting them into changes in electrical excitability, be these changes due to synaptic remodeling, metabolic cues, toxic breakdown products, hormonal signals of wakefulness, or even cell-intrinsic processes. Furthermore, how Cv-c might read sleep pressure signals and facilitate or convert this into electrical properties is unclear, although one potential clue may lie in Cv-c’s previously described role in synaptic homeostasis at the neuromuscular junction (Pilgram et al., 2011). Nevertheless, the model has the potential to unify myriad observations in Drosophila sleep studies. For example, Cv-c may regulate trafficking or channel properties of the sleep-relevant Shaker postassium channel or Sleepless within FB neurons, adding cellular specificity to these mutant phenotypes. Or perhaps Cv-c modulates cAMP/PKA signaling, which has been implicated in fly sleep homeostasis as well as dopamine inhibition of FB neurons. The model may also hint at possible mechanisms to explain other unusual observations. For example, starvation or methamphetamine sleep deprives flies without apparent rebound ( Andretic et al.