The Drosophila fragile X mental retardation gene regulates sleep need.
The Drosophila fragile X mental retardation gene regulates sleep need.
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DOI：
10.1523/jneurosci.4830-08.2009
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发表时间：
2009-02-18
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影响因子：
--
通讯作者：
Cirelli C
中科院分区：
文献类型：
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作者：
Bushey D;Tononi G;Cirelli C
睡眠需求受发育阶段和神经元可塑性的影响，但其潜在机制尚不清楚。脆性X智力低下基因Fmr1的功能缺失突变导致人类最常见的遗传性智力低下，它参与突触发生和突触可塑性，其表达取决于发育阶段和清醒经验。Fmr1在不同物种中高度保守，携带dFmr1功能缺失或功能获得突变的果蝇突变体具有很好的特征：非晶型突触生长过度，树突起较大，修剪发育缺陷，神经传递增强，而超晶型则表现出相反的缺陷，包括树突和轴突分支不足以及突触分化丧失。我们在这里发现，dFmr1变形者是长睡眠者，多形体是短睡者，而两者都表现出更多的运动活动和更短的寿命。非晶态者和多形者也表现出异常的睡眠稳态，在睡眠剥夺后，醒觉能力受损，睡眠没有反弹。睡眠昼夜节律的障碍不能解释dFmr1突变体睡眠表型的改变，也不能解释谷氨酸能代谢性受体的异常激活。此外，在整个蘑菇体中过表达dFmr1足以减少睡眠。最后，dFmr1蛋白水平受发育阶段和行为状态的调节，在eClosure后立即表达增加，在长时间清醒后表达增加。因此，dFmr1的表达对睡眠和突触都有剂量依赖性的影响，这表明dFmr1突变体的睡眠时间的变化可能源于突触生理的变化。
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 life-span. 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.