[Background] Chronic stress does not trigger depression in all individuals, as some remain resilient. However, the underlying mechanisms that contribute to stress sensitivity have been poorly understood. We found that Shati/Nat8l, N-acetyltransferase, levels increased in the dorsal striatum of stress-susceptible mice exposed repeated social defeat stress (RSDS). In the present study, we revealed the mechanism of regulation in stress sensitivity by Shati/Nat8l.
[Methods] C57BL/6J male mice were exposed RSDS using ICR mice, and the susceptible or resilient group were classified by social interaction test. We generated dorsal striatal Shati/Nat8l overexpression (STR-Shati OE) or knockdown mice (STR-Shati KD). These mice were assessed depression-like behaviors after RSDS. We investigated the relationship between Shati/Nat8l and serotonin in the striatum by pharmacological regulation of serotonergic system and in vivo microdialysis.
[Results] Striatal serotonin decreased in stress susceptible, not resilient mice. STR-Shati OE showed the vulnerability to social stress. Conversely, STR-Shati KD showed the resilience to social stress. The reduction of striatal serotonin was observed in STR-Shati OE. The vulnerability to stress in Shati OE recovered by modulation of serotonergic system.
[Conclusions] Striatal Shati/Nat8l controls stress sensitivity via regulation of serotonin in the striatum. Our study suggested the novel mechanisms underlying stress sensitivity, and striatal Shati/Nat8l could be a new target for medical tools for depression.