Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia: a mechanism for antipsychotic drug action?
Differential expression of metabotropic glutamate receptors 2 and 3 in schizophrenia: a mechanism for antipsychotic drug action?
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DOI：
10.1176/appi.ajp.2009.08091445
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Tamminga CA
中科院分区：
文献类型：
--
作者：
Ghose S;Gleason KA;Potts BW;Lewis-Amezcua K;Tamminga CA
临床前和临床数据提示II组代谢型谷氨酸受体（mGluR2和mGluR3）参与精神分裂症的病理生理。此外，最近的一项II期临床试验已经证明了mGluR2/3激动剂的抗精神病疗效。本研究旨在区分mGluR2和mGluR3受体蛋白在精神分裂症中的表达，并定量谷氨酸羧肽酶II (GCPII)，以探讨代谢受体在精神分裂症治疗中的作用。GCPII是一种代谢n -乙酰天冬氨酸（NAAG）的酶，NAAG是哺乳动物大脑中唯一已知的mGluR3的特异性内源性激动剂。使用特异性抗体检测mGluR2、mGluR3和GCPII在人死后脑10个区域的正常表达水平。然后在15例精神分裂症患者和正常对照者的背外侧前额叶（DLPFC）、颞叶（TC）和运动皮层（MC）中检测每种蛋白的表达水平差异。通过对啮齿动物进行慢性抗精神病治疗，研究抗精神病药物对这3种蛋白表达的潜在影响。我们发现在mGluR2蛋白水平不变的情况下，精神分裂症患者DLPFC中GCPII蛋白显著增加，mGluR3蛋白显著减少。啮齿动物慢性抗精神病药物治疗不影响GCPII或mGluR3水平。DLPFC中GCPII表达增加和mGluR3表达降低表明精神分裂症患者该脑区中naag介导的信号通路受损。此外，这些数据暗示mGluR3受体参与mGluR2/3激动剂的抗精神病作用。
Preclinical and clinical data implicate the group II metabotropic glutamate receptors (mGluR2 and mGluR3) in the pathophysiology of schizophrenia. Moreover, a recent phase II clinical trial has demonstrated the antipsychotic efficacy of a mGluR2/3 agonist. The current study was designed to distinguish the expression of mGluR2 and mGluR3 receptor protein in schizophrenia and to quantify glutamate carboxypeptidase II (GCPII) in order to explore a role for the metabotropic receptors in schizophrenia therapeutics. GCPII is an enzyme that metabolizes N-acetylaspartylglutamate (NAAG), the only known specific endogenous agonist of mGluR3 in the mammalian brain. The normal expression levels of mGluR2, mGluR3 and GCPII were determined in 10 regions of the human post mortem brain using specific antibodies. Differences in expression levels of each protein were then examined in the dorsolateral prefrontal (DLPFC), temporal (TC) and motor cortex (MC) in 15 matched cases of schizophrenia and normal controls. Chronic antipsychotic treatment in rodents was conducted to examine the potential effect of antipsychotic drugs on expression of the 3 proteins. We found a significant increase in GCPII protein and a reduction in mGluR3 protein in the DLPFC in schizophrenia with mGluR2 protein levels unchanged. Chronic antipsychotic treatment in rodents did not influence GCPII or mGluR3 levels. Increased GCPII expression and low mGluR3 expression in the DLPFC suggest that NAAG-mediated signaling is impaired in this brain region in schizophrenia. Further, these data implicate the mGluR3 receptor in the antipsychotic action of mGluR2/3 agonists.
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DOI：
10.1080/00207450802330702
发表时间：
2008-11
期刊：
The International journal of neuroscience
影响因子：
--
作者：
Ghose S;Crook JM;Bartus CL;Sherman TG;Herman MM;Hyde TM;Kleinman JE;Akil M
通讯作者：
Akil M
影响因子：
17.7
作者：
Callicott, JH;Mattay, VS;Weinberger, DR
通讯作者：
Weinberger, DR
影响因子：
7.6
作者：
Ghose, S;Weickert, CS;Kleinman, JE
通讯作者：
Kleinman, JE
影响因子：
7.6
作者：
Lahti, AC;Weiler, MA;Tamminga, CA
通讯作者：
Tamminga, CA
影响因子：
2.9
作者：
Ohishi, H;Neki, A;Mizuno, N
通讯作者：
Mizuno, N