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

doi:10.3389/fnmol.2018.00121

	GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1
	Zhou, Dongsheng 1,5; Lv, Dan 1,2,4; Wang, Zhen3 ; Zhang, Yanhua 1,2,4; Chen, Zhongming 5; Wang, Chuang 1,2,4
刊名	FRONTIERS IN MOLECULAR NEUROSCIENCE
	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
DOI	10.3389/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.
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
WOS研究方向	Neurosciences & Neurology
语种	英语
出版者	FRONTIERS MEDIA SA
WOS记录号	WOS:000429707100001
内容类型	期刊论文
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).