4 Discussion
The crucial discoveries of this
research are as follows. Initially, the concentration of D-serine was
decreased in depression susceptible mice in NAc. Secondly, D-serine
produced antidepressant-like effects in the FST, TST and CSDS model.
Thirdly, chronic treatment of D-serine could restore the stress-induced
increase in NAc BDNF signaling cascade. Next, reduced levels of D-Serine
in the NAc contribute to impaired synaptic plasticity. Together,
we have demonstrated for the first
time that D-serine has beneficial effects through suppression of the
BDNF signaling pathway and regulation of synaptic adaptations in NAc
against depression. This discovery is extremely exciting and interesting
as it has provided an original underlying antidepressant.
D-serine can pass through the blood-brain barrier, and we have
simultaneously completed the in vivo experiment of intraperitoneal
injection. Our data showed that D-serine has capabilities common to
traditional antidepressants in the FST and TST. In these tests, mice
were under stressful circumstances from which they could not escape, and
would become helpless and immobile after a premier period of striving,
which is similar to human depression and could be reversed by
antidepressant pharmaceuticals. As expected, the reduction of immobility
in the FST and TST induced by acute injection of D-serine in mice was
not codirectional by an increase in locomotor activity of mice,
indicating that D-serine indeed has a potential interest for the
treatment of depression. We further used the CSDS model to make sure the
outcomes of D-serine, as the CSDS model has great predictive validity
the symptomatology of stress-related disorders like depression(K. Zhang
et al., 2020). The sucrose preference test is an indicatrix of the
anhedonia-like behavioral alterations. Our consequences demonstrated
that D-serine administration fully renovated the sucrose preference of
CSDS-stressed mice to normal level. Another marked symptom of depression
is social elusion, meaning that depressed rodents are passive and
tempting to get away from the world. Our results bespoken that D-serine
administration also reversed the social avoidance of CSDS-stressed mice,
like fluoxetine. Collectively, these discoveries demonstrate that
D-serine could be developed into a novel antidepressant.
Moreover, the discovery that D-serine could reverse the CSDS-induced
effects on the NAc BDNF signaling cascade is infusive. This research is
the premier to provide experimental evidence representing that D-serine
has effects on the BDNF system in NAc. In this research, we found that
chronic administration of D-serine down-regulated level of BDNF,
phosphorylated TrkB and phosphorylated CREB in the NAc of stressed mice,
to the basal level of saline-treated mice. Moreover, the antidepressant
effects induced by D-serine administration were also facilitated by
co-treatment with K252a, a potent inhibitor of the BDNF receptor TrkB.
Synaptic plasticity is regarded as a cellular substrate of learning and
memory(Kamalova, Futai, Delpire, & Nakagawa, 2020). D-Serine is
considerable for the activation of NMDAR-dependent synaptic
plasticity(Cha, Lee, & Lee, 2020). NAC neurons are among those that
lightly express LTD, which is susceptible to stress. We found that
D-serine facilitated LTD. It has been confirmed that D-Serine in NAc
modulates drug addiction through synaptic plasticity(Liu et al., 2016).
It is well known that drug addiction and depression are regulated by NAc
and are two opposite behaviors.
Our results support that LTD was
markedly damaged in the NAc of CSDS mice and was reversed by a chronic
injection of D-serine. LTD is induced by low rises of the intracellular
Ca2+ concentration(Bezprozvanny & Hiesinger, 2013).
Reduced Ca2+ influx at post-synaptic level with
hypofunction of NMDAR could persuasively explain the damage of LTD in
our CSDS model. So, our results
manifested that the decrease of D-serine levels in the NAc of CSDS mice
hindered the induction of NMDAR-dependent LTD. By electrophysiological
techniques, our consequences sustain the NMDAR-LTD molecular substrate
that convey this lack of plasticity in CSDS and could work out new
targets for antidepressants.
In summary, the results of this study reveal that D-serine possesses
antidepressant-like effects in mice, which appeared to be mediated
through down-regulation of the NAc BDNF-TrkB signaling pathway. In
addition, it indicates that chronic social defeat stress treatment can
alter the metabolism of D-serine in the NAc, leading to both reduced
D-serine levels and the impairment of NMDAR dependent LTD.
Moreover,
increasing the content of D-serine in NAC can improve depression.
Therefore, this provides a new insight to see the pharmacological
outcomes of D-serine and illuminating the development of new
antidepressants with higher effectiveness and fewer side reaction.
Furthermore, related experiments such as SR-shRNA, DAAO-shRNA, NMDAR
blocker MK-801, NR2B-shRNA and so on by us are in progress at the same
time.
ACKNOWLEDGEMENTS
This work was supported by grants from the National Natural Science
Funds of China (Grant No. 81760256 and 81960256) to Dr. Wei Wang. The
study also received support by Academic and technical leaders of major
disciplines Foundation (20204BCJL22049) and Natural Science
Foundation (Grant No. 20192BAB205038) of Jiangxi, China to Dr. Wei Wang.