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Tsc1 突变型浦肯野细胞小鼠的自闭症样行为和小脑功能障碍。

Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.

机构信息

The F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

出版信息

Nature. 2012 Aug 30;488(7413):647-51. doi: 10.1038/nature11310.

Abstract

Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.

摘要

自闭症谱系障碍(ASD)是一种高发的神经发育障碍,但其潜在的发病机制仍不清楚。最近的研究表明小脑与这些疾病有关,ASD 患者的尸检研究显示小脑浦肯野细胞(PC)丢失,而孤立性小脑损伤与更高的 ASD 发病率有关。然而,小脑对 ASD 发病机制的贡献程度仍不清楚。结节性硬化症(TSC)是一种遗传疾病,其 ASD 的合并发病率很高,这是由于 TSC1 或 TSC2 的突变所致,其蛋白产物二聚化并负调控哺乳动物雷帕霉素靶蛋白(mTOR)信号。TSC 是一个研究小脑对 ASD 潜在发病机制贡献的有趣模型,因为最近对 TSC 患者的研究表明小脑病理学与 ASD 症状的增加相关。功能成像还显示,与没有 ASD 的 TSC 患者相比,患有 ASD 的 TSC 患者的深部小脑结构显示代谢亢进。然而,到目前为止,还没有研究 Tsc1 的作用以及 Tsc1 功能障碍的后果在小脑中的作用。在这里,我们发现 Tsc1 在小鼠小脑 PC 中的杂合和纯合缺失都会导致类似自闭症的行为,包括异常的社会互动、重复行为和发声,以及 PC 兴奋性降低。用 mTOR 抑制剂雷帕霉素治疗突变小鼠可预防病理和行为缺陷。这些发现表明 Tsc1 在 PC 功能中有新的作用,并为小脑对自闭症等认知障碍的贡献定义了一个分子基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1ff/3615424/f73e6a709564/nihms-384647-f0001.jpg

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