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The Journal of Neuroscience, February 18, 2009, 29(7):1948-1961; doi:10.1523/JNEUROSCI.4830-08.2009

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Development/Plasticity/Repair
The Drosophila Fragile X Mental Retardation Gene Regulates Sleep Need

Daniel Bushey, Giulio Tononi, and Chiara Cirelli

Department of Psychiatry, University of Wisconsin–Madison, Madison, Wisconsin 53719

Correspondence should be addressed to Dr. Chiara Cirelli, Department of Psychiatry, University of Wisconsin–Madison, 6001 Research Park Boulevard, Madison, WI 53719. Email: ccirelli{at}wisc.edu

Sleep need is affected by developmental stage and neuronal plasticity, but the underlying mechanisms remain unclear. The fragile X mental retardation gene Fmr1, whose loss-of-function mutation causes the most common form of inherited mental retardation in humans, is involved in synaptogenesis and synaptic plasticity, and its expression depends on both developmental stage and waking experience. Fmr1 is highly conserved across species and Drosophila mutants carrying dFmr1 loss-of-function or gain-of-function mutations are well characterized: amorphs have overgrown dendritic trees with larger synaptic boutons, developmental defects in pruning, and enhanced neurotransmission, while hypermorphs show opposite defects, including dendritic and axonal underbranching and loss of synapse differentiation. We find here that dFmr1 amorphs are long sleepers and hypermorphs are short sleepers, while both show increased locomotor activity and shortened lifespan. Both amorphs and hypermorphs also show abnormal sleep homeostasis, with impaired waking performance and no sleep rebound after sleep deprivation. An impairment in the circadian regulation of sleep cannot account for the altered sleep phenotype of dFmr1 mutants, nor can an abnormal activation of glutamatergic metabotropic receptors. Moreover, overexpression of dFmr1 throughout the mushroom bodies is sufficient to reduce sleep. Finally, dFmr1 protein levels are modulated by both developmental stage and behavioral state, with increased expression immediately after eclosure and after prolonged wakefulness. Thus, dFmr1 expression dose-dependently affects both sleep and synapses, suggesting that changes in sleep time in dFmr1 mutants may derive from changes in synaptic physiology.

Key words: Drosophila; synaptic plasticity; dFmr1; Fmr1; fragile X; FMRP; sleep; lifespan

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Received Oct. 7, 2008; revised Dec. 9, 2008; accepted Dec. 9, 2008.

Correspondence should be addressed to Dr. Chiara Cirelli, Department of Psychiatry, University of Wisconsin–Madison, 6001 Research Park Boulevard, Madison, WI 53719. Email: ccirelli{at}wisc.edu

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