PMID- 29550603 OWN - NLM STAT- MEDLINE DCOM- 20190910 LR - 20190910 IS - 1872-9754 (Electronic) IS - 0197-0186 (Linking) VI - 116 DP - 2018 Jun TI - Deletion of serine racemase confers D-serine -dependent resilience to chronic social defeat stress. PG - 43-51 LID - S0197-0186(18)30023-8 [pii] LID - 10.1016/j.neuint.2018.03.008 [doi] AB - 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. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Dong, Chao AU - Dong C AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba, 260-8670, Japan. FAU - Zhang, Ji-Chun AU - Zhang JC AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba, 260-8670, Japan. FAU - Ren, Qian AU - Ren Q AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba, 260-8670, Japan. FAU - Ma, Min AU - Ma M AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba, 260-8670, Japan. FAU - Qu, Youge AU - Qu Y AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba, 260-8670, Japan. FAU - Zhang, Kai AU - Zhang K AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba, 260-8670, Japan. FAU - Yao, Wei AU - Yao W AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba, 260-8670, Japan. FAU - Ishima, Tamaki AU - Ishima T AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba, 260-8670, Japan. FAU - Mori, Hisashi AU - Mori H AD - Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. FAU - Hashimoto, Kenji AU - Hashimoto K AD - Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Chiba, 260-8670, Japan. Electronic address: hashimoto@faculty.chiba-u.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180314 PL - England TA - Neurochem Int JT - Neurochemistry international JID - 8006959 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Drinking Water) RN - 452VLY9402 (Serine) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Depression/*drug therapy/metabolism/physiopathology MH - Depressive Disorder/*drug therapy/physiopathology MH - Disease Models, Animal MH - Drinking Water MH - Hippocampus/drug effects/metabolism MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Nucleus Accumbens/drug effects/metabolism MH - Serine/genetics/metabolism/*pharmacology MH - Stress, Psychological/*metabolism OTO - NOTNLM OT - D-Serine OT - Depression OT - Serine racemase OT - Stress resilience EDAT- 2018/03/20 06:00 MHDA- 2019/09/11 06:00 CRDT- 2018/03/19 06:00 PHST- 2018/01/17 00:00 [received] PHST- 2018/02/07 00:00 [revised] PHST- 2018/03/13 00:00 [accepted] PHST- 2018/03/20 06:00 [pubmed] PHST- 2019/09/11 06:00 [medline] PHST- 2018/03/19 06:00 [entrez] AID - S0197-0186(18)30023-8 [pii] AID - 10.1016/j.neuint.2018.03.008 [doi] PST - ppublish SO - Neurochem Int. 2018 Jun;116:43-51. doi: 10.1016/j.neuint.2018.03.008. Epub 2018 Mar 14.