TheDrosophilaFragile X Mental Retardation Gene Regulates Sleep Need

Abstract

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.

Sleep and Development in Genetically Tractable Model Organisms

“…Fly models of fragile X syndrome (FXS) display aberrant circadian output (Dockendorff et al 2002) and sleep. In particular, flies with a loss-of-function mutation in dFmr1 display high sleep need (Bushey et al 2009), perhaps with a specific abnormality of sleep ontogenetic change. Recent work indicates abnormal sleep in a fly model of neurofibromatosis 1 (NF1) (Bai and Sehgal 2015), and NF1 has previously been implicated in circadian output circuitry .…”

Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

“…The MBs, functionally analogous to the mammalian hippocampus, are essential for different types of behavior, such as sleep, associative learning, and memory (Davis 1993;Roman and Davis 2001;Joiner et al 2006). The MBs contain the neuronal population required to regulate normal sleep activity; overexpression of dFmr1 in the MBs reduced the prolonged sleep episodes of mutant flies (Bushey et al 2009). In another recent study, dFmr1 mutants showed a deeper night-like sleep phenotype during the day, which was regulated by two molecules, dFMRP and cAMP (van Alphen et al 2013).…”

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

“…We first examined synapse connectivity in the central brain, based on well-established dfmr1 phenotypes. dfmr1 null mutants exhibit strikingly abnormal circadian rhythm patterns, with a complete loss of rhythmicity in the absence of environmental entrainment (Bushey et al, 2009;Dockendorff et al, 2002;Inoue et al, 2002;Sofola et al, 2008). Although Fmr1 knockout mice show only mild impairments, the Fmr1/Fxr2 double knockout is likewise entirely arrhythmic (Zhang et al, 2008).…”