Drosophila HyperkineticMutants Have Reduced Sleep and Impaired Memory

Abstract

In mammals, sleep is thought to be important for health, cognition, and memory. Fruit flies share most features of mammalian sleep, and a recent study found that Drosophila lines carrying loss-of-function mutations in Shaker (Sh) are short sleeping, suggesting that the Sh current plays a major role in regulating daily sleep amount. The Sh current is potentiated by a ␤ modulatory subunit coded by Hyperkinetic (Hk). Here, we demonstrate that severe loss-of-function mutations of Hk reduce sleep and do so primarily by affecting the Sh current. Moreover, we prove, using a transgenic approach, that a wild-type copy of Hk is sufficient to restore normal sleep. Furthermore, we show that short-sleeping Hk mutant lines have a memory deficit, whereas flies carrying a weaker hypomorphic Hk allele have normal sleep and normal memory. By comparing six short-sleeping Sh lines with two normal sleeping ones, we also found that only alleles that reduce sleep also impair memory. These data identify a gene, Hk, which is necessary to maintain normal sleep, and provide genetic evidence that short sleep and poor memory are linked.Key words: Drosophila; sleep; learning; memory; Shaker; hyperkinetic IntroductionSleep is thought to be important for health, cognition, and memory (Horne, 1988;Bonnet and Arand, 1997;Durmer and Dinges, 2005). Many features of sleep are shared between mammals and fruit flies. As in mammals, sleep in Drosophila consists of long periods of behavioral immobility with increased arousal threshold (Hendricks et al., 2000;Shaw et al., 2000), is associated with changes in brain electrical activity (Nitz and Tononi, 2002) and gene expression (Cirelli et al., 2005a;Zimmerman et al., 2006), is reduced by caffeine and stimulants (Shaw et al., 2000;Hendricks et al., 2003a;Andretic et al., 2005), and becomes fragmented with aging (Koh et al., 2006). In both mammals and flies, sleep is homeostatically regulated, because its duration and intensity increase with the duration of previous waking (Huber et al., 2004), and sleep deprivation (SD) results in reduced performance (Huber et al., 2004).In a recent study, we found that Sh mns flies, which carry a point mutation in a conserved Shaker (Sh) domain, sleep only 3-4 h/d, whereas their wild-type controls sleep 8 -14 h/d (Cirelli et al., 2005b). After crossing out genetic modifiers accumulated over many generations, we found that other Sh alleles become short sleepers and fail to complement the short sleeping Sh mns phenotype, suggesting that the Sh current is responsible for the short sleeping phenotype. The Sh locus encodes the ␣ subunit of a tetrameric potassium channel that passes a voltage-activated fastinactivating (I A ) current (Schwarz et al., 1988). Sh orthologs (K v ) occur in vertebrates (Littleton and Ganetzky, 2000) and, in both mammals and flies, play a major role in the control of membrane repolarization and transmitter release (Schwarz et al., 1988). Hyperkinetic (Hk) encodes a ␤ subunit that binds to each ␣ subunit in the Sh tetramer ( Fig. 1), and its presenc...

Heterochromatin remodeling by CDK12 contributes to learning in Drosophila

“…The decreased expression of neuronal genes in the adult brain prompted us to test whether the loss of CDK12 or CycK would have any effect on neuronal behaviors. Because the potassium channel genes Sh, Hk, eag, and SK and the cAMP phosphodiesterase dnc are all known to be involved in Drosophila learning and memory (19,(22)(23)(24)(25), we performed a courtship conditioning test using an OK107-GAL4 driver, which is mainly active in the MBs (putative learning and memory centers in the Drosophila brain). Unsuccessful courtship reduces the subsequent courtship behavior of male flies toward virgin females, and this courtship conditioning behavior is known as one of the major learning and memory paradigms in Drosophila.…”

Acute Sleep Deprivation Blocks Short- and Long-Term Operant Memory inAplysia

“…[10][11][12] In Drosophila and mouse models, genetic mutants exhibiting reduced sleep also show impairments in memory. [13][14][15] However, increasing sleep, either pharmacologically or genetically, can enhance learning and memory in suboptimal situations. 16,17 Neither the effects of sleep deprivation nor the role of sleep in the induction and consolidation of memories are well understood at the neuronal or molecular level.…”

Control of sleep by a network of cell cycle genes

“…Recent work in Drosophila has demonstrated that knockdown of Cdk1 significantly reduces seizure duration in both bang sensitive (bas) and bang senseless (bss) mutants, 25 27 slow delayed rectifier potassium channel, 28 nicotinic acetylcholine receptor, 29 and GABA A receptor, 30,31 respectively, are all implicated in sleep and may be potential phosphorylation targets of Cdk1.…”