Cerebellar contribution to autism-relevant behaviors in fragile X syndrome models.
Cerebellar contribution to autism-relevant behaviors in fragile X syndrome models.
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DOI：
10.1016/j.celrep.2023.113533
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发表时间：
2023-12-26
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
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小脑功能障碍与自闭症谱系障碍（ASD）有关。尽管在脆性X综合征（FXS）患者和该疾病的小鼠模型中观察到小脑病理学，但小脑功能对FXS中ASD相关行为的贡献尚未完全表征。在这项研究中，我们证明了一个关键小脑的作用，为Fmr1（脆性X信使核糖核蛋白1）在ASD相关的行为。首先，我们确定减少社会行为，感觉超敏反应，小脑功能障碍，小脑Fmr1的损失。然后，我们证明，小脑特异性表达的Fmr1是足以影响社会，感觉，小脑功能障碍，并在全球Fmr1突变体中观察到的大脑皮层兴奋性过强的表型。此外，我们证明，针对ASD牵连小脑区域Crus1改善小脑特异性和全球Fmr1突变体的行为。总之，这些结果表明小脑对FXS相关行为的贡献至关重要，并对未来的治疗策略产生影响。吉布森等人证明小脑Fmr 1的缺失导致社会行为减少、感觉超敏反应和小脑功能障碍。在全球Fmr1突变体，小脑特异性表达的Fmr1是足以改变观察到的表型。此外，靶向ASD相关的小脑区域Crus1改善了小脑特异性和全局Fmr1突变体的行为。
Cerebellar dysfunction has been linked to autism spectrum disorders (ASDs). Although cerebellar pathology has been observed in individuals with fragile X syndrome (FXS) and in mouse models of the disorder, a cerebellar functional contribution to ASD-relevant behaviors in FXS has yet to be fully characterized. In this study, we demonstrate a critical cerebellar role for Fmr1 (fragile X messenger ribonucleoprotein 1) in ASD-relevant behaviors. First, we identify reduced social behaviors, sensory hypersensitivity, and cerebellar dysfunction, with loss of cerebellar Fmr1. We then demonstrate that cerebellar-specific expression of Fmr1 is sufficient to impact social, sensory, cerebellar dysfunction, and cerebro-cortical hyperexcitability phenotypes observed in global Fmr1 mutants. Moreover, we demonstrate that targeting the ASD-implicated cerebellar region Crus1 ameliorates behaviors in both cerebellar-specific and global Fmr1 mutants. Together, these results demonstrate a critical role for the cerebellar contribution to FXS-related behaviors, with implications for future therapeutic strategies. Gibson et al. demonstrate that loss of cerebellar Fmr1 leads to reduced social behaviors, sensory hypersensitivity, and cerebellar dysfunction. In global Fmr1 mutants, cerebellar-specific expression of Fmr1 is sufficient to alter observed phenotypes. Moreover, targeting the ASD-implicated cerebellar region Crus1 ameliorates behaviors in both cerebellar-specific and global Fmr1 mutants.
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DOI：
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