Background and Purpose: D-serine is a crucial endogenous co-agonist of NMDARs in the central nervous system and can affect the function of the BDNF system, which plays an essential role in modulating synaptic plasticity. The aim of the current investigation was to systematically evaluate the role and mechanisms of D-serine in depressive behavior in NAc. Experimental Approach: D-Serine concentration in the CSDS model in NAc was measured by HPLC. The antidepressant-like effects of D-serine were identified by the FST and TST in control mice, and then assessed in the CSDS model. We applied social interaction and sucrose preference tests to identify the susceptibility of CSDS model. Western blotting was further performed to assess the changes of BDNF signaling cascade in NAc after CSDS and D-serine treatment. The BDNF signaling inhibitor (K252a) was also used to clarify the antidepressant mechanism of D-serine. Moreover, effects of D-serine on synaptic plasticity in NAc were investigated by electrophysiological methods. Key Results: D-serine injections into the NAc exhibited antidepressant effects in the FST, TST and CSDS model. Next, D-serine down-regulated the BDNF signaling pathway in NAc during the CSDS procedure. Moreover, K252a enhanced the antidepressant effects of D-serine. We also found that D-serine was essential for NMDARs-LTD. Conclusion and Implications: Our results provide the first evidence that D-serine exerts antidepressant effects in mice mediated through restraining the BDNF signaling pathway and regulating synaptic plasticity in NAc, which indicates that D-serine may be an effective therapeutic agent for depression. KEYWORDS D-serine, depression, NAc, BDNF, CSDS, LTD