Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland; Institute for Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
Biol Psychiatry. 2021 Jun 1;89(11):1058-1072. doi: 10.1016/j.biopsych.2020.10.012. Epub 2020 Oct 27.
The serine-threonine kinase mTORC1 (mechanistic 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.
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 D dopamine receptor (D1R) signaling. The effect of persistently elevated mTORC1 was confirmed using D1-Cre to elevate mTORC1 activity in D1R neurons.
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.
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.
丝氨酸-苏氨酸激酶 mTORC1（雷帕霉素靶蛋白复合物 1）对于正常细胞功能至关重要，但在遗传发育性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存在争议。
本研究检查了表达 Rheb 的转基因模型中的行为，Rheb 是已知的 mTORC1 的最接近的激活剂，并且在持续升高的 mTORC1 信号模型中对纹状体磷酸蛋白质组学进行了分析。生物化学、免疫组织化学、电生理学和行为方法用于研究持续升高的 mTORC1 对 D 多巴胺受体 (D1R) 信号的影响。使用 D1-Cre 来升高 D1R 神经元中的 mTORC1 活性，以确认持续升高的 mTORC1 的影响。
我们报告说，持续升高的 mTORC1 信号阻断了依赖于 DARPP-32（多巴胺和 cAMP 调节的神经元磷酸蛋白）的经典 D1R 信号。mTORC1 的直接下游效应物核糖体 S6 激酶 1（S6K1）磷酸化并激活 DARPP-32。持续升高的 mTORC1-S6K1 阻断了 DARPP-32 下游的动态 D1R 信号，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以及 D1R 行为反应，包括社交能力。与升高的 mTORC1-S6K1 相关，人类疾病患者大脑中的 mTORC1-DARPP-32 阻断的候选生物标志物增加，支持该机制在认知疾病中的作用。
mTORC1-S6K1 与 D1R 信号的交集为理解病理性 mTORC1 激活对神经精神疾病中行为症状的影响提供了分子框架。
