BACKGROUND The serine-threonine kinase mTORC1 (mammalian target of rapamycin complex 1) is essential for normal cell function but is aberrantly activated in the brain in both genetic-developmental and sporadic diseases and is associated with a spectrum of neuropsychiatric symptoms. The underlying molecular mechanisms of cognitive and neuropsychiatric symptoms remain controversial. METHODS The present study examines behaviors in transgenic models that express Rheb, the most proximal known activator of mTORC1, and profiles striatal phosphoproteomics in a model with persistently elevated mTORC1 signaling. Biochemistry, immunohistochemistry, electrophysiology, and behavior approaches are used to examine the impact of persistently elevated mTORC1 on D1 dopamine receptor (D1R) signaling. The effect of persistently elevated mTORC1 was confirmed using D1-Cre to elevate mTORC1 activity in D1R neurons. RESULTS We report that persistently elevated mTORC1 signaling blocks canonical D1R signaling that is dependent on DARPP-32 (dopamine- and cAMP-regulated neuronal phosphoprotein). The immediate downstream effector of mTORC1, ribosomal S6 kinase 1 (S6K1), phosphorylates and activates DARPP-32. Persistent elevation of mTORC1-S6K1 occludes dynamic D1R signaling downstream of DARPP-32 and blocks multiple D1R responses, including dynamic gene expression, D1R-dependent corticostriatal plasticity, and D1R behavioral responses including sociability. Candidate biomarkers of mTORC1-DARPP-32 occlusion are increased in the brain of human disease subjects in association with elevated mTORC1-S6K1, supporting a role for this mechanism in cognitive disease. CONCLUSIONS The mTORC1-S6K1 intersection with D1R signaling provides a molecular framework to understand the effects of pathological mTORC1 activation on behavioral symptoms in neuropsychiatric disease.

中文翻译：

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持续升高的 mTORC1-S6 激酶 1 破坏 DARPP-32 依赖性 D1 多巴胺受体信号传导和行为

背景丝氨酸-苏氨酸激酶 mTORC1（雷帕霉素复合物 1 的哺乳动物靶点）对于正常细胞功能至关重要，但在遗传发育和散发性疾病的大脑中异常激活，并与一系列神经精神症状相关。认知和神经精神症状的潜在分子机制仍然存在争议。方法 本研究检查了表达 Rheb（已知最接近的 mTORC1 激活剂）的转基因模型中的行为，并在 mTORC1 信号持续升高的模型中分析纹状体磷酸蛋白质组学。生物化学、免疫组织化学、电生理学和行为方法用于检查持续升高的 mTORC1 对 D1 多巴胺受体 (D1R) 信号传导的影响。使用 D1-Cre 证实了持续升高的 mTORC1 的影响，以提高 D1R 神经元中的 mTORC1 活性。结果 我们报告持续升高的 mTORC1 信号传导阻断了依赖于 DARPP-32（多巴胺和 cAMP 调节的神经元磷蛋白）的典型 D1R 信号传导。mTORC1 的直接下游效应子，核糖体 S6 激酶 1 (S6K1)，磷酸化并激活 DARPP-32。mTORC1-S6K1 的持续升高阻断了 DARPP-32 下游的动态 D1R 信号传导，并阻断了多种 D1R 反应，包括动态基因表达、D1R 依赖性皮质纹状体可塑性和 D1R 行为反应，包括社交性。mTORC1-DARPP-32 闭塞的候选生物标志物在人类疾病受试者的大脑中与 mTORC1-S6K1 升高有关，支持这种机制在认知疾病中的作用。结论 mTORC1-S6K1 与 D1R 信号的交叉为了解病理性 mTORC1 激活对神经精神疾病行为症状的影响提供了一个分子框架。