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.