痫蛋白功能异常在衰老海马突触可塑性及认知损害中的作用及机制

Cognitive decline is a hallmark of the aging process and synaptic plasticity deficits are deemed as its biological basis. Previous studies have demonstrated that changes in AMPAR number and/or function are a core feature of aging-associated synaptic plasticity and cognitive decline; regulating the function of AMPARs can reverse the impairments in synaptic plasticity and cognition. Stargazin is a principal regulator of AMPAR trafficking. It is physiologically nitrosylated to enhance its binding to GluR1 and then increase the surface expression of GluR1-containing AMPARs. Our preliminary experiments have found that the level of S-nitrosylated stargazin and the binding of stargazin to GluR1 in the hippocampus of cognitively impaired aged rats were much lower than those of adult and cognitively unimpaired aged rats. Therefore, we propose that the dysfunction of stargazin might contribute to aging-associated hippocampal synaptic plasticity and cognitive impairments, and promoting the S-nitrosylation of stargazin in the hippocampus of impaired aged rats would reverse the cognitive deficits via increasing the surface expression of GluR1 subunit. In this project, we investigated the role of decreased S-nitrosylation of stargazin in the synaptic plasticity and cognitive deficits in aged rats with cognitive impairments, and the influence of promoting S-nitrosylation of stargazin on aging-associated cognitive deficits using molecular biological, electrophysiological and behavioral techniques. We hope to further elucidate the molecular mechanism of cognitive aging, proposing a new strategy for the treatment of aging-associated cognitive disorders.

认知减退是脑衰老的重要标志，突触可塑性缺陷是其生物学基础。研究显示，AMPA受体功能异常是衰老突触可塑性和认知减退的核心特征，调节该受体功能可逆转衰老突触及认知损伤。痫蛋白是调节AMPA 受体转运的重要蛋白，其功能受亚硝基化修饰状态的影响。申请者实验发现：与认知健全老年鼠相比，认知损害老年鼠海马组织痫蛋白亚硝基化水平、痫蛋白与AMPA 受体GluR1亚基的结合明显降低。本项目据此提出：痫蛋白功能异常导致AMPA受体转运缺陷可能是衰老海马突触可塑性及认知损害的重要原因；调节痫蛋白亚硝基化，可通过促进AMPA受体突触转运逆转衰老认知功能损伤。本项目拟利用分子生物学、神经电生理和动物行为学技术，研究衰老认知障碍中海马组织痫蛋白亚硝基化的变化情况及其在衰老突触可塑性和认知缺陷中的作用；同时探讨调节痫蛋白亚硝基化对衰老认知功能的影响，以期进一步揭示衰老认知损害的机理，为衰老认知障碍的治疗提供新策略。

随着人口老龄化加重，衰老相关认知功能障碍已成为影响我国人民身体健康的重要问题，但迄今为止，衰老认知损害尚缺乏有效的治疗手段，亟待阐明其病理机制，为该病的治疗提供新策略。认知减退是脑衰老的重要标志，突触可塑性缺陷是其生物学基础。研究显示，谷氨酸受体功能异常是衰老突触可塑性和认知减退的核心特征，调节该受体功能可逆转衰老突触及认知损伤。本课题围绕谷氨酸受体功能调节因子硫化氢（H2S）和一氧化氮合酶的内源性抑制剂ADMA在衰老及相关疾病的认知功能障碍方面开展了一系列研究，结果如下：①衰老大鼠杏仁核区H2S含量下降，补充H2S可逆转衰老所致的杏仁核突触可塑性和恐惧记忆缺陷，其机制与H2S修复谷氨酸NMDA受体GluN2B亚基功能有关，提示补充H2S可能是治疗老年相关认知障碍的潜在途径；②阿尔茨海默病（AD）模型小鼠海马区H2S含量降低，慢性腹腔注射H2S供体可通过上调海马GluN2B亚基的突触膜表达及NMDA受体功能进而逆转AD小鼠的认知及突触可塑性缺陷，该研究进一步阐述了H2S改善AD认知功能的分子机制；③抑制H2S合成酶CBS可导致杏仁核区LTP抑制和大鼠恐惧记忆损害，其机制与NMDA受体功能调节有关，表明内源性H2S信号参与正常认知过程；④ADMA是一氧化氮合酶的内源性抑制剂。既往研究显示，精神分裂症患者血浆ADMA含量显著减低。我们发现，非典型抗精神病药物可改善精神分裂症患者认知功能，其程度与血浆ADMA水平变化有关，提示ADMA可能是精神分裂症认知改善评估的生物学标记物；⑤精神分裂症患者血浆H2S含量显著低于正常对照人群，其含量与患者一般病理症状、工作记忆、视觉记忆和执行功能存在相关性，提示H2S信号异常参与精神分裂症精神病理及认知损害过程，血浆H2S可能是精神分裂症潜在的生物学标记物；⑥血清胰岛素样生长因子1（IGF-1）含量下降与精神分裂症患者认知损害相关联，表明IGF-1信号异常参加精神分裂症认知损害过程。