[Background] The number of patients with depression is increasing, but the cause of the onset remains unclear. We found that exposure of social defeat stress to Shati/Nat8l increased its expression only in the striatum. Shati/Nat8l has N-acetyltransferase activity and synthesizes N-acetylaspartic acid (NAA) from L-aspartic acid and acetyl-CoA. One of the causes of depression is the BDNF hypothesis, and there are reports that the expression level of BDNF is epigenetically regulated. Since Shati/Nat8 uses acetyl-CoA, which is necessary for acetylation, as a substrate, we focused on the regulation of acetylation of BDNF and performed this study to clarify the relationship with Shati/Nat8l.
[Methods/Results] BDNF levels in the striatum of mice exposed to social defeat stress for 10 days were measured, and mRNA levels increased. Furthermore, BDNF histone acetylation was also measured by chromatin immunoprecipitation, and an increase was observed. Shati/Nat8l striatal local KO mice were found to be resistant to social defeat stress in various behavioral experiments.
[Discussion] We found that the reduction of Shati/Nat8l in the mouse striatum plays an important role in the development of resistance to depression-like behavior. Part of the mechanism is thought to be through regulation of BDNF acetylation. There are few reports on the relationship between the striatum and the onset of depression, and the results of this study indicate the possibility of Shati/Nat8l as a therapeutic target for depression in the future.