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GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1

文献类型：期刊论文

作者Zhou, Dongsheng1,5; Lv, Dan1,2,4; Wang, Zhen3; Zhang, Yanhua1,2,4; Chen, Zhongming5; Wang, Chuang1,2,4
刊名FRONTIERS IN MOLECULAR NEUROSCIENCE
出版日期2018-04-11
卷号11
关键词GLYX-13 disrupted-in-schizophrenia 1 N-methyl-D-aspartate receptor N-methyl D-aspartate receptor subtype 2B schizophrenia
ISSN号1662-5099
DOI10.3389/fnmol.2018.00121
文献子类Article
英文摘要Background: Evidence supports that the hypofunction of N-methyl-D-aspartate receptor (NMDAR) and downregulation of disrupted-in-schizophrenia 1 (DISC1) contribute to the pathophysiology of schizophrenia. N-Methyl D-aspartate receptor subtype 2B (NR2B)-containing NMDAR are associated with cognitive dysfunction in schizophrenia. GLYX-13 is an NMDAR glycine-site functional partial agonist and cognitive enhancer that does not induce psychotomimetic side effects. However, it remains unclear whether NR2B plays a critical role in the GLYX-13-induced alleviation of schizophrenia-like behaviors in mice. Methods: The effect of GLYX-13 was tested by observing changes in locomotor activity, novel object recognition ability, and prepulse inhibition (PPI) induced by dizocilpine (known as MK-801) in mice. Lentivirus-mediated NR2B knockdown in the hippocampus was assessed to confirm the role of NR2B in GLYX-13 pathophysiology, using Western blots and immunohistochemistry. Results: The systemic administration of GLYX-13 (0.5 and 1 mg/kg, i.p.) ameliorates MK-801 (0.5 mg/kg, i.p.)-induced hyperlocomotion, deficits in memory, and PPI in mice. Additionally, GLYX-13 normalized the MK-801-induced alterations in signaling molecules, including NR2B and DISC1 in the hippocampus. Furthermore, we found that NR2B knockdown produced memory and PPI deficits without any changes in locomotor activity. Notably, DISC1 levels significantly decreased by NR2B knockdown. However, the effective dose of GLYX-13 did not alleviate the memory and PPI dysfunctions or downregulation of DISC1 induced by NR2B knockdown. Conclusion: Our results suggest GLYX-13 as a candidate for schizophrenia treatment, and NR2B and DISC1 in the hippocampus may account for the molecular mechanisms of GLYX-13.
WOS关键词NMDA RECEPTOR HYPOFUNCTION ; LONG-TERM DEPRESSION ; COGNITIVE IMPAIRMENT ; SUBCHRONIC PHENCYCLIDINE ; MODELING SCHIZOPHRENIA ; ALLOSTERIC MODULATORS ; PREPULSE INHIBITION ; ANTIPSYCHOTIC-LIKE ; PREFRONTAL CORTEX ; D-SERINE
资助项目National Natural Science Foundation of China[81671337] ; National Natural Science Foundation of China[81201050] ; Natural Science Foundation of Zhejiang province[LQ12H09001] ; Natural Science Foundation of Zhejiang Province[Y14H090014] ; Natural Science Foundation of Ningbo[2017A610212] ; Ningbo Municipal Innovation Team of Life Science and Health[2015C110026] ; National Undergraduate Training Program for Innovation and Entrepreneurship[201711646017] ; Student Research and Innovation Program[00000000] ; Ningbo University[00000000]
WOS研究方向Neurosciences & Neurology
语种英语
WOS记录号WOS:000429707100001
出版者FRONTIERS MEDIA SA
源URL[http://119.78.100.183/handle/2S10ELR8/279806]  
专题药物化学研究室
通讯作者Chen, Zhongming; Wang, Chuang
作者单位1.Ningbo Univ, Ningbo Key Lab Behav Neurosci, Sch Med, Ningbo, Zhejiang, Peoples R China;
2.Ningbo Univ, Sch Med, Zhejiang Prov Key Lab Pathophysiol, Ningbo, Zhejiang, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai, Peoples R China
4.Ningbo Univ, Sch Med, Dept Physiol & Pharmacol, Ningbo, Zhejiang, Peoples R China;
5.Ningbo Kangning Hosp, Ningbo, Zhejiang, Peoples R China;
推荐引用方式
GB/T 7714		 Zhou, Dongsheng,Lv, Dan,Wang, Zhen,et al. GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1[J]. FRONTIERS IN MOLECULAR NEUROSCIENCE,2018,11.
APA Zhou, Dongsheng,Lv, Dan,Wang, Zhen,Zhang, Yanhua,Chen, Zhongming,&Wang, Chuang.(2018).GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1.FRONTIERS IN MOLECULAR NEUROSCIENCE,11.
MLA Zhou, Dongsheng,et al."GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1".FRONTIERS IN MOLECULAR NEUROSCIENCE 11(2018).

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来源：上海药物研究所

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