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.