Effect and mechanism of suberoylanilide hydroxamic acid on fear extinction in mice with chronic social defeat stress

Abstract

Objective To investigate the effect and mechanism of suberoylanilide hydroxamic acid(SAHA) on the fear extinction in mice with chronic social defeat stress (SD). Methods Fifty-six male C57BL/6J mice aged 7-8 weeks were randomly divided into control group, social defeat group, control-SAHA group and social defeat-SAHA group to investigate the effect of SAHA and social defeat group, social defeat-AAV BDNF group and social defeat-AAV blank group to investigate the effect of BDNF. Fear extinction in mice was evaluated by fear conditioning test (FC). The levels of BDNF and HDAC2 in mice hippocampus were detected by Western blot (WB). The expression of BDNF-overexpressing virus in hippocampus of mice was detected by immunofluorescence assay. Results (1)Compared with control group, fear extinction in the social defeat group was significantly decreased (P<0.05). Compared with control group, the level of HDAC2(0.50±0.02)in the social defeat group was significantly increased (P<0.001), while the level of BDNF(0.16±0.03)was significantly decreased (P<0.001) in the social defeat group. (2)After using SAHA, fear extinction of mice significantly improved (P<0.05). Compared with control group, the level of HDAC2 (0.26±0.02) in the control-SAHA group was significantly decreased(P<0.001), and the level of BDNF (0.40±0.03) was significantly increased (P<0.001). Compared with social defeat group, the level of HDAC2 (0.39±0.03) in the social defeat-SAHA group was significantly decreased (P<0.001), and the level of BDNF (0.28±0.01) was significantly increased (P<0.001). (3)After injection BDNF-overexpressing virus, fear extinction was significantly improved(P<0.05). Conclusion SAHA can enhance fear extinction in mice with chronic social defeat stress and its mechanism may be related to the up-regulation of BDNF expression in hippocampus by inhibiting HDAC2 in hippocampal. Key words: Suberoylanilide hydroxamic acid, histone deacetylases inhibitor; Brain-derived neurotrophic factor; Chronic stress; Fear extinction; Social defeat