Striatal Shati/Nat8l–BDNF pathways determine the sensitivity to social defeat stress in mice through epigenetic regulation

The global number of patients with depression increases in correlation to exposure to social stress. Chronic stress does not trigger depression in all individuals, as some remain resilient. The underlying molecular mechanisms that contribute to stress sensitivity have been poorly understood, although revealing the regulation of stress sensitivity could help develop treatments for depression. We previously found that striatal Shati/Nat8l, an N-acetyltransferase, was increased in a depression mouse model. We investigated the roles of Shati/Nat8l in stress sensitivity in mice and found that Shati/Nat8l and brain-derived neurotrophic factor (BDNF) levels in the dorsal striatum were increased in stress-susceptible mice but not in resilient mice exposed to repeated social defeat stress (RSDS). Knockdown of Shati/Nat8l in the dorsal striatum induced resilience to RSDS. In addition, blockade of BDNF signaling in the dorsal striatum by ANA-12, a BDNF-specific receptor tropomyosin-receptor-kinase B (TrkB) inhibitor, also induced resilience to stress. Shati/Nat8l is correlated with BDNF expression after RSDS, and BDNF is downstream of Shati/Nat8l pathways in the dorsal striatum; Shati/Nat8l is epigenetically regulated by BDNF via histone acetylation. Our results demonstrate that striatal Shati/Nat8l-BDNF pathways determine stress sensitivity through epigenetic regulation. The striatal Shati/Nat8l-BDNF pathway could be a novel target for treatments of depression and could establish a novel therapeutic strategy for depression patients.