D-serine has antidepressant effects in mice through suppression of the
BDNF signaling pathway and regulation of synaptic plasticity in the
nucleus accumbens
Abstract
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