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(KowiaĆski
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.