NSF蛋白亚硝基化修饰所介导的GluA2 containing-AMPA受体膜稳定性在卒中后抑郁中的作用及机制研究

谷氨酸系统与脑卒中及抑郁症关系密切，其中AMPA受体参与二者的发病过程，但其介导卒中后抑郁的发病机制尚不完全清楚。我们前期研究发现卒中后抑郁模型前额叶皮层中AMPA受体 的亚基GluA2表达减少，稳定GluA2膜表达的NSF蛋白的亚硝基化水平降低，参与亚硝基化的气体NO含量减少。为进一步探讨AMPA受体介导卒中后抑郁的发病机制，我们提出假设，在卒中后抑郁模型中，前额叶皮层nNOS表达降低，导致NO生成减少，NSF蛋白被NO亚硝基化修饰的水平降低，继而导致其与GluA2结合能力减弱，突触后膜AMPA受体表达减少，损伤了突触传递功能导致抑郁。为验证该假说：一方面，我们应用电生理、多肽干预等技术，明确AMPA受体介导卒中后抑郁的发生；另一方面，应用基因沉默、免疫共沉淀等技术探讨调控AMPA受体从而介导卒中后抑郁的分子机制。本研究为揭示AMPA受体参与卒中后抑郁发病机制提供理论依据。

Glutamatergic neurotransmission is directly or indirectly involved in the pathophysiology and treatment of storke and mood disorders. AMPA receptor has been demonstrated to have a role in storke and mood disorders. However, the role   of AMPA receptor in the pathogenesis of Post-stroke depression (PSD) is not clear. Our previous study found that the expression of GluA2 subunit, the levels of S-nitrosylation of NSF and the production of NO were decreased in mPFC in PSD. To further explore the mechanism of PSD pathogenesis. We propose the hypothesis that in PSD model, the expression of nNOS is decreased, which reduces the production of NO. As a result of reduced NO, the levels of S-nitrosylation of NSF and its binding to GluA2 subunit are also decreased. Furthermore, decreased surface expression of AMPA receptor reduces synaptic transmission which mediates the pathogenesis of PSD. In order to verify the hypothesis: We will use electrophysiological and peptide intervention technology to clarify whether AMPA receptor mediates the pathogenesis of PSD; On the other hand, use gene silencing and immunoprecipitation technique to investigate the molecular regulation mechanism of AMPA receptor in the pathogenesis of PSD. This study will help us to understand the mechanism of AMPA receptor in the pathophysiology of PSD from a brand new angle.