mTOR Suppresses Macroautophagy During Striatal Postnatal Development and Is Hyperactive in Mouse Models of Autism Spectrum Disorders
mTOR Suppresses Macroautophagy During Striatal Postnatal Development and Is Hyperactive in Mouse Models of Autism Spectrum Disorders
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DOI：
10.3389/fncel.2020.00070
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发表时间：
2020-03-31
影响因子：
5.3
通讯作者：
Santini, Emanuela
中科院分区：
文献类型：
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作者：
Lieberman, Ori J.;Cartocci, Veronica;Santini, Emanuela
巨细胞自噬（Macroautophagy，以下简称自噬）在神经元发育和退化过程中起着重要作用。在这里，我们研究了自噬是否在纹状体中受到发育调控，纹状体是一个与神经发育疾病有关的大脑区域。我们证明，自噬通量抑制纹状体出生后的发展，出生后第28天左右（P28）达到成人水平。我们还发现，mTOR信号，自噬的关键调节器，在同一发育时期增加。我们进一步表明，mTOR信号转导负责通过调节Beclin-1和VPS 34活性来抑制自噬。最后，我们发现，自噬是下调在纹状体后期出生后的发展（P28）在子宫内暴露于丙戊酸（VPA），自闭症谱系障碍（ASD）的小鼠模型的小鼠。暴露于VPA的小鼠也显示出纹状体神经传递和社会行为的缺陷。VPA暴露小鼠中过度活跃的mTOR信号传导的纠正恢复了社会行为。这些结果表明，神经元选择代谢信号级联来发育调节自噬，并提供了额外的证据表明mTOR依赖性信号通路代表ASD小鼠模型中在特定出生后窗口期间活跃的致病性信号级联。
Macroautophagy (hereafter referred to as autophagy) plays a critical role in neuronal function related to development and degeneration. Here, we investigated whether autophagy is developmentally regulated in the striatum, a brain region implicated in neurodevelopmental disease. We demonstrate that autophagic flux is suppressed during striatal postnatal development, reaching adult levels around postnatal day 28 (P28). We also find that mTOR signaling, a key regulator of autophagy, increases during the same developmental period. We further show that mTOR signaling is responsible for suppressing autophagy, via regulation of Beclin-1 and VPS34 activity. Finally, we discover that autophagy is downregulated during late striatal postnatal development (P28) in mice with in utero exposure to valproic acid (VPA), an established mouse model of autism spectrum disorder (ASD). VPA-exposed mice also display deficits in striatal neurotransmission and social behavior. Correction of hyperactive mTOR signaling in VPA-exposed mice restores social behavior. These results demonstrate that neurons coopt metabolic signaling cascades to developmentally regulate autophagy and provide additional evidence that mTOR-dependent signaling pathways represent pathogenic signaling cascades in ASD mouse models that are active during specific postnatal windows.