Abstract
Background and Purpose: D-serine is a crucial endogenous co-agonist of N-methyl-D-aspartate receptors (NMDARs) in the central nervous system and can affect the function of the brain derived neurotrophic factor (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 nucleus accumbens (NAc).
Experimental Approach: D-Serine concentration in the chronic social defeat stress (CSDS) model in NAc was measured by high-performance liquid chromatography (HPLC). With fluoxetine as the positive control, the antidepressant-like effects of D-serine were identified by the forced swim test (FST) and tail suspension test (TST) in control mice, and then assessed in the CSDS model. We applied behavioral tests of 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-like mechanism of D-serine. Moreover, effects of D-serine on synaptic plasticity in NAc were investigated by electrophysiological methods.
Key Results: The concentration of D-serine was decreased in depression susceptible mice in NAc. D-serine injections into the nucleus accumbens exhibited antidepressant-like effects in the FST and TST without affecting the locomotor activity of mice. D-serine was also effective in the CSDS model of depression. Moreover, D-serine down-regulated the BDNF signaling pathway in NAc during the CSDS procedure. Furthermore, BDNF signaling inhibitor (K252a) enhanced the antidepressant effects of D-serine. We also found that D-serine was essential for NMDARs-dependent long-term depression (LTD).
Conclusion and Implications: Our results provide the first evidence that D-serine exerts antidepressant-like 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.