GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1.
GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1.
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GLYX-13 改善 MK-801 诱导的小鼠精神分裂症样表型：海马 NR2B 和 DISC1 的作用
DOI：
10.3389/fnmol.2018.00121
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发表时间：
2018
影响因子：
4.8
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Zhou D;Lv D;Wang Z;Zhang Y;Chen Z;Wang C
背景资料：有证据表明，N-甲基-D-天冬氨酸受体（NMDAR）功能低下和DISC 1下调参与了精神分裂症的病理生理过程。含N-甲基D-天冬氨酸受体亚型2B（NR 2B）的NMDAR与精神分裂症的认知功能障碍相关。GLYX-13是一种NMDAR甘氨酸位点功能性部分激动剂和认知增强剂，不诱导拟精神病副作用。然而，目前尚不清楚NR 2B是否在GLYX-13诱导的小鼠精神分裂症样行为的缓解中起关键作用。研究方法：GLYX-13的作用通过观察小鼠的自发活动、新物体识别能力和地佐环平（称为MK-801）诱导的前脉冲抑制（PPI）的变化来测试。使用蛋白质印迹和免疫组织化学评估海马中慢病毒介导的NR 2B敲低以确认NR 2B在GLYX-13病理生理学中的作用。结果：全身施用GLYX-13（0.5和lmg/kg，i. p.）MK-801（0.5mg/kg，i.p.）在小鼠中诱导过度运动、记忆缺陷和PPI。此外，GLYX-13使MK-801诱导的信号分子改变正常化，包括海马中的NR 2B和DISC 1。此外，我们发现NR 2B敲低产生记忆和PPI缺陷，而运动活性没有任何变化。值得注意的是，DISC 1水平通过NR 2B敲低而显著降低。然而，有效剂量的GLYX-13并没有缓解NR 2B敲低诱导的记忆和PPI功能障碍或DISC 1下调。结论：我们的研究结果表明GLYX-13作为精神分裂症治疗的候选者，并且海马中的NR 2B和DISC 1可能解释GLYX-13的分子机制。
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.
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