基于KYN和FKN双信号通路研究胶质细胞激抑失衡致糖尿病并发抑郁症海马“Quad-Partite”突触可塑性损伤机制及中药干预

Diabetes mellitus with depression (DD) is an insidious, relapsing and highly lethal disease. Previous studies showed hippocampal synaptic plasticity damage was closely related to the occurrence of DD, but its mechanism is not clear yet. Previous studies have found the inflammatory environment in the hippocampus of DD rats could reduce the structure and function of the hippocampal microglia (Mg) and astrocytes (As) were changed, showing an imbalance state of agitation and inhibition, and glutamate receptor(NR) was overactivated. The latast researches show that the "Quad-Partite" synapse combines MG, As, presynapticelement and postsynapticelement into one structural unit to systematically elucidate the characteristics and regularity of synaptic injury, while NR is the valve molecule of synaptic plasticity. Consequently, the subject intends to further investigate the molecular mechanism of DD which associated with the imbalance of Mg-As stimulation in hippocampal "Quad-Partite" synapse in diabetic state triggers inflammatory cascade reactions, resulting in the abnormal KYN and FKN dual signal pathways, which together mediate NR over-stimulation and cause damages of hippocampal synaptic plasticity, and further complicates DD, on the whole - cell aspect and morphology - function - molecular level by the modern technologies of patch clamp, LSC, HCS and FCM etc.. The theory of “enriching yin and nourishing qi, disperse blood stasis and resolve depression” was applied to disproof the pathology (asthenia, stasis and depression) of DD, which could provide a novel ideas for the research of its pathogenesis and prevention.

糖尿病并发抑郁症（DD）发病隐匿、易反复且致死率高。海马突触可塑性损伤与DD发生密切相关，但机制未明。课题组前期发现，DD大鼠海马炎症环境可诱发小胶质细胞（MG）、星形胶质细胞（As）呈激抑失衡状态，谷氨酸受体（NR）被过度激活。最新研究表明，“Quad-Partite”突触将MG、As、突触前膜和后膜构成一个结构整体单元可系统阐明突触损伤的特点与规律，而NR是其可塑性的阀门分子。因此，本课题拟综合运用膜片钳、LSC、HCS、FCM等现代技术，从整体-细胞两方面、形态-功能-分子三水平，探明“糖尿病时，海马‘Quad-Partite’突触MG-As激抑失衡触发炎症级联反应，导致KYN和FKN双信号通路异常，共同介导NR过激致海马突触可塑性损伤，进而并发DD”的分子机制，并采用“滋阴益气、化瘀解郁”立法方药干预反证DD“虚、瘀、郁”的中医病机，可为其发病机制和有效防治提供新思路。

糖尿病并发抑郁症(DD)发病隐匿、易反复且致死率高，海马突触可塑性损伤与DD发生密切相关，但其机制未明。课题组前期发现DD大鼠海马炎症环境可诱发小胶质细胞(MG)、星形胶质细胞(As)呈激抑失衡状态，并致KYN和FKN双信号过度激活谷氨酸受体(NR)。由于NR过激是介导DD海马“Quad-Partite”可塑性损伤的阀门分子，故本研究推测：MG-As激抑失衡引起KYN和FKN双信号通路异常，共同介导NR过激致海马“Quad-Partite”突触可塑性损伤，是DD发生发展的关键病机。.本研究采用模拟临床发病特点和规律的DD动物模型及其细胞模型为研究对象，分别从体内、体外两方面，探讨KYN和FKN双信号介导NR过激致DD海马“Quad-Partite”突触损伤的分子机制及益气滋阴、化瘀解郁的中药复方左归降糖解郁方的干预机制。结果表明，糖尿病状态下，海马MG中Iba-1、As中GFAP均过度表达，炎性因子IL-1β、IL-6、TNF-α水平升高，造成KYN和FKN双信号通路传导与信息传递异常，共同激活NR2A、NR2B致海马“Quad-Partite”突触形态、基础结构及可塑性功能损伤，进而诱发DD；而左归降糖解郁方能有效改善MG-As激抑失衡，并通过调控KYN和FKN双信号以修复海马“Quad-Partite”突触可塑性损伤，从而发挥治疗DD的作用。.综上，本研究阐明了“虚、瘀、郁”病机状态下，KYN和FKN双信号通路介导的NR过激致DD海马“Quad-Partite”突触可塑性损伤，最终诱发DD的分子机制。同时进一步明确了左归降糖解郁方治疗DD的作用环节及潜在靶点，为DD有效防治提供新思路。