海马α-突触核蛋白在抑郁症中的作用及机制研究

Major depressive disorder (MDD) is a common, chronic, and recurrent mental disease with high morbidity, high recurrence and high disability rate, which brings heavy burden on individual, family and society. Previous studies have shown that α-synuclein may be involved in the etiology of depression, and we also found that the expression of α-synuclein was abnormal in the peripheral blood and hippocampus of depression. Hippocampus plays an important role in the depression disorder, so the abnormal expression of α-synuclein in hippocampus may affect the occurrence of depression disorder. However, the mechanisms underlying this effect remain poorly characterized. In this study, we will use adeno-associated virus vector combined with depression animal model to explore the effect and function of α-synuclein in the hippocampus in vivo and in vitro. Moreover, we will illuminate the impact of α-synuclein in the occurrence of MDD as well as its pathogenic mechanisms, which provide the theory basis for the comprehension and treatment of the depression occurrence.

重度抑郁症是一种常见的慢性复发性精神疾病，具有高患病率、高复发率、高致残率等特点，给个人、家庭和社会带来了沉重的负担。已有研究表明α-突触核蛋白可能参与了抑郁症的发生，在我们前期的工作中也发现α-突触核蛋白在抑郁症患者外周血和抑郁症小鼠海马中均出现异常表达，海马作为与抑郁症发病密切相关的脑区，α-突触核蛋白在海马中的异常表达可能是影响抑郁症发病的重要原因，但是α-突触核蛋白在海马及抑郁症致病机制中的作用依然不清楚。因此，本课题拟采用腺相关病毒载体特异性表达α-突触核蛋白并结合抑郁症动物模型，通过体内和体外实验探讨α-突触核蛋白在海马中的作用和功能，阐明α-突触核蛋白对抑郁症疾病发生的影响及其作用机制，为进一步了解抑郁症的发生及治疗提供理论依据。

由SNCA编码的α-突触核蛋白(α-syn)在神经递质传递、囊泡功能和神经可塑性中发挥着关键作用。研究发现SNCA与重度抑郁症（MDD）的发生相关，然而，SNCA在抑郁症中的发病机制依然不清楚。在本研究中，我们报道了SNCA在抑郁症(MDD)患者和抑郁小鼠的外周血中上调，同时慢性束缚应激(CRS)也引起海马中SNCA的表达升高。在非应激条件下，小鼠海马中过表达SNCA会导致小鼠产生抑郁样行为，而敲除SNCA可以逆转CRS诱导的小鼠抑郁样行为。我们通过进一步研究发现SNCA可能通过补体介导的小胶质细胞吞噬和炎症反应导致海马突触丢失和神经元细胞死亡，从而参与抑郁症的发生。综上，海马SNCA和补体系统参与了抑郁症的发生，为抑郁症的发生提供了一个新的视角。