Rap1a regulates CUMS-induced neuroinflammation and cognitive dysfunction and emotional abnormalities in mice.

Rap1a is a member of the Ras family of proteins and first came into view as an immune modulator of cells, playing roles in both innate and adaptive immunity. It is widely distributed in various tissue cells and is closely related to multiple biological functions of cells, including immunity, proliferation, differentiation, adhesion, and angiogenesis. Homocysteine (HCY) is a sulfur-containing non-essential amino acid that does not participate in protein synthesis. It is mainly converted from exogenously ingested methionine into cysteine through a series of metabolic reactions. Recent studies have found that HCY can promote the high expression of Rap1a in hepatocytes. In addition, Rap1a can also promote HCY-mediated autophagy in hepatocytes. Meanwhile, our previous research results have shown that the content of HCY in the plasma and hippocampus of mice increases during the process of chronic stress-induced cognitive dysfunction and emotional abnormalities. Therefore, we aim to investigate the role of the HCY-Rap1a in chronic stress-induced neuroinflammation. Interestingly, we found that HCY intervention in BV2 cells can increase the expression of Rap1a, thereby inducing neuroinflammation; however, in BV2 cells with Rap1a knockdown, HCY intervention did not cause significant inflammatory responses. Moreover, we knocked down Rap1a in the mouse hippocampus and subjected the mice to chronic stress intervention. The results showed that knocking down Rap1a can ameliorate cognitive dysfunction and emotional abnormalities and neuroinflammation induced by CUMS. These findings suggest that modulating the expression of Rap1a may serve as a potential therapeutic strategy to ameliorate neuroinflammation in stress-related mental disorders.