1 Introduction
Depression is a mental disorder characterized by notable, persistent and life-threatening mood disorders, and it is projected to be a major reason for disability worldwide by 2030 according to published reports from the World Health Organization(He et al., 2019). It causes huge social and economic consequences(Jin, Cui, Zhao, Fan, & Li, 2019). In the past few decades, there has not yet been a highly efficient drug for treating depression(D. Li et al., 2020). Therefore, it is very necessary to develop more reliable antidepressants with fewer side effects.
BDNF is distributed throughout the central nervous system(Arora, Sharma, & Singh, 2020). Currently, a leading hypothesis of depression suggests that the BDNF signaling pathway is closely implicated in the pathophysiology of depression(Caroleo et al., 2019). Phosphorylation and activation of cAMP response element binding protein (CREB) induced by BDNF binding to tyrosine kinase B (TrkB) receptor on the cell membrane(Bai, Zhang, Zhou, Li, & Bai, 2019). CREB is a crucial transcription factor in the brain which regulates the biosynthesis of numerous pro-survival proteins, including BDNF(Alhusaini et al., 2020). We have testified that the level of activity of the BDNF signaling pathway is increased in the NAc of CSDS mice, whereas chronic antidepressant treatment could reverse these pathological changes(B. Jiang et al., 2014).These researches manifest that suppression of the NAc BDNF signaling pathway could offer a novel method to the therapy of depression.
BDNF plays an essential role in modulating synaptic plasticity(KowiaƄski et al., 2018; Tomassoni-Ardori et al., 2019). Development of depression has been ascribed to disfunction of the reward pathway, in which the NAc plays a key role(Lorsch et al., 2018). Chronic stress has been recorded to cause drastic neurochemical changes in the NAc, leading to depressive phenotypes(Shirayama & Chaki, 2006). Our research has confirmed that synaptic adaptability in the NAc is the key to mediate depression(B Jiang et al., 2013; M. Li et al., 2018). NMDAR- LTD in the NAc as prime regulators in the remodeling of excitatory synapses and lingering psychomotor springiness in response to psychostimulant. D-serine is a crucial endogenous co-agonist of NMDARs in the central nervous system and has been recorded to influence the function of the BDNF system. It was found that CSDS exposure destabilized the D-serine in the NAc(Wook Koo et al., 2016). This destabilization constitutes a continued molecular adaptability of excitatory synapses to chronic stress, leading to the corresponding development of behavioral plasticity. Accumulating evidence reveals the impairment of NMDAR-dependent LTD in the NAc of animal models of depression(Belujon & Grace, 2014).
In short, BDNF system and synaptic plasticity in NAc are closely related to depression, and D-serine affects the function of BDNF system and synaptic plasticity in NAc. However, there is no detailed study on the role of BDNF system and synaptic plasticity in NAc in D-serine-mediated antidepressant mechanism. The aim of the current investigation was to systematically evaluate the role of D-serine on depression behaviors considered to be mediated by the BDNF system and in LTD in the NAc.