The fragile X autosomal homolog 1 (Fxr1) is regulated by lithium and has been GWAS‐associated with schizophrenia and insomnia. Homeostatic regulation of synaptic strength is essential for the maintenance of brain functions and involves both cell‐autonomous and system‐level processes such as sleep. We examined the contribution of Fxr1 to cell‐autonomous homeostatic synaptic scaling and neuronal responses to sleep loss, using a combination of gene overexpression and Crispr/Cas9‐mediated somatic knockouts to modulate gene expression. Our findings indicate that Fxr1 is downregulated during both scaling and sleep deprivation via a glycogen synthase kinase 3 beta (GSK3β)‐dependent mechanism. In both conditions, downregulation of Fxr1 is essential for the homeostatic modulation of surface AMPA receptors and synaptic strength. Preventing the downregulation of Fxr1 during sleep deprivation results in altered EEG signatures. Furthermore, sequencing of neuronal translatomes revealed the contribution of Fxr1 to changes induced by sleep deprivation. These findings uncover a role of Fxr1 as a shared signaling hub between cell‐autonomous homeostatic plasticity and system‐level responses to sleep loss, with potential implications for neuropsychiatric illnesses and treatments.

中文翻译：

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Fxr1 调节睡眠和突触稳态。

脆弱的 X 常染色体同源物 1 (Fxr1) 受锂调节，并且 GWAS 与精神分裂症和失眠相关。突触强度的稳态调节对于维持大脑功能至关重要，并且涉及细胞自主和系统级过程（例如睡眠）。我们结合基因过表达和 Crispr/Cas9 介导的体细胞敲除来调节基因表达，研究了 Fxr1 对细胞自主稳态突触缩放和神经元对睡眠不足的反应的贡献。我们的研究结果表明，Fxr1 在缩放和睡眠剥夺期间通过糖原合酶激酶 3 beta (GSK3β) 依赖性机制下调。在这两种情况下，Fxr1 的下调对于表面 AMPA 受体和突触强度的稳态调节至关重要。在睡眠剥夺期间防止 Fxr1 下调会导致脑电图特征改变。此外，神经元翻译组测序揭示了 Fxr1 对睡眠剥夺引起的变化的贡献。这些发现揭示了 Fxr1 作为细胞自主稳态可塑性和系统级对睡眠不足的反应之间的共享信号中枢的作用，对神经精神疾病和治疗具有潜在影响。