Dysregulation of AMPK-mTOR signaling leads to comorbid anxiety in Dip2a KO mice
Dysregulation of AMPK-mTOR signaling leads to comorbid anxiety in Dip2a KO mice
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AMPK-mTOR 信号传导失调导致 Dip2a KO 小鼠共病焦虑
DOI：
10.1093/cercor/bhac393
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发表时间：
2022-10-13
期刊：
影响因子：
3.7
通讯作者：
Yu, Hua-Li
中科院分区：
文献类型：
--
作者：
Ma, Jun;Li, Kai;Yu, Hua-Li
自闭症通常与其他精神疾病共存。我们之前已经证明 Dip2a 敲除 (KO) 会诱导小鼠出现类似自闭症的行为。然而，Dip2a 在其他精神疾病中的作用仍不清楚。在本文中，我们发现 Dip2a KO 小鼠患有共病焦虑。 Dip2a KO 导致皮质和海马兴奋性神经元的树突长度减少。分子机制研究表明 AMPK 过度激活并抑制 mTOR 级联，导致树突形态缺陷。成年海马神经元中 Dip2a 的缺失（Dip2a 条件性敲除 (cKO)）会增加急性应激暴露时焦虑的易感性。应用 mTOR 抑制剂 (2R,6R)-羟基去甲氯胺酮 (HNK) 可以挽救 Dip2a KO 和 Dip2a cKO 小鼠的焦虑样行为。此外，6周的高脂肪饮食摄入减轻了Dip2a KO小鼠和Dip2a cKO小鼠的AMPK-mTOR信号传导并减轻了焦虑的严重程度。总而言之，这些结果揭示了 DIP2A 通过调节 AMPK-mTOR 信号传导在焦虑病理生理学中的未被识别的功能。
Autism is often comorbid with other psychiatric disorders. We have previously shown that Dip2a knockout (KO) induces autism-like behaviors in mice. However, the role of Dip2a in other psychiatric disorders remains unclear. In this paper, we revealed that Dip2a KO mice had comorbid anxiety. Dip2a KO led to a reduction in the dendritic length of cortical and hippocampal excitatory neurons. Molecular mechanism studies suggested that AMPK was overactivated and suppressed the mTOR cascade, contributing to defects in dendritic morphology. Deletion of Dip2a in adult-born hippocampal neurons (Dip2a conditional knockout (cKO)) increased susceptibility to anxiety upon acute stress exposure. Application of (2R,6R)-hydroxynorketamine (HNK), an inhibitor of mTOR, rescued anxiety-like behaviors in Dip2a KO and Dip2a cKO mice. In addition, 6 weeks of high-fat diet intake alleviated AMPK-mTOR signaling and attenuated the severity of anxiety in both Dip2a KO mice and Dip2a cKO mice. Taken together, these results reveal an unrecognized function of DIP2A in anxiety pathophysiology via regulation of AMPK-mTOR signaling.