The N-methyl-D-aspartate receptor (NMDAR) plays a key role in the pathophysiology of depression. Serine racemase (SRR, encoded by Srr) converts L-serine to D-serine, an endogenous co-agonist at the glycine site of the NMDAR. Knock-out (KO) of Srr did not alter behavioral signs of depression compared with wild-type (WT) mice as evaluated by locomotion, tail suspension, forced swimming, and 1% sucrose preference tests. However, chronic social defeat stress (CSDS: 10 days) caused a depression-like phenotype as measured by these same tests in WT mice but not in Srr KO mice, suggesting that decreased D-serine co-agonist activity confers resilience against CSDS. In WT mice, CSDS decreased brain-derived neurotrophic factor (BDNF) expression and phosphorylation/activation of its receptor TrkB in prefrontal cortex (PFC), dentate gyrus (DG), and the CA3 region of the hippocampus, but increased BDNF and phosphorylated TrkB in the nucleus accumbens (NAc). Conversely, CSDS did not alter BDNF or TrkB phosphorylation in any brain region of Srr KO mice. Administration of D-serine through drinking water (600 mg/L for 20 days) 10 days prior to and during CSDS restored the depression-like phenotype in Srr KO mice. These findings suggest that reducing brain D-serine may improve stress resilience, thereby reducing depression risk.

所述Ñ甲基d天冬氨酸受体（NMDAR）起着在抑郁症的病理生理学中起关键作用。丝氨酸消旋酶（SRR，由Srr编码）将L-丝氨酸转化为D-丝氨酸，D-丝氨酸是NMDAR甘氨酸位点的内源性协同激动剂。通过运动，尾巴悬吊，强迫游泳和1％蔗糖偏爱试验评估，与野生型（WT）小鼠相比，Srr的敲除（KO）不会改变抑郁的行为迹象。然而，通过这些相同的测试，在WT小鼠中而不是在Srr中，慢性社交挫败压力（CSDS：10天）导致了抑郁样表型。KO小鼠表明D丝氨酸共激动剂活性降低，赋予了抗CSDS的抗性。在野生型小鼠中，CSDS降低了脑源性神经营养因子（BDNF）的表达以及其受体TrkB在前额叶皮层（PFC），齿状回（DG）和海马CA3区的磷酸化/激活，但增加了BDNF和磷酸化的TrkB在伏伏核（NAc）中。相反，CSDS不会改变Srr KO小鼠任何大脑区域的BDNF或TrkB磷酸化。在CSDS之前和期间通过饮水（600 mg / L，持续20天）施用D-丝氨酸可恢复Srr KO小鼠的抑郁样表型。这些发现表明，减少脑D-丝氨酸可提高应激弹性，从而降低抑郁风险。