Matosin Natalie, Fernandez-Enright Francesca, Lum Jeremy S, Andrews Jessica L, Engel Martin, Huang Xu-Feng, Newell Kelly A
Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia; Schizophrenia Research Institute, Sydney, NSW 2010, Australia.
Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; Faculty of Social Sciences, University of Wollongong, Wollongong, NSW 2522, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia; Schizophrenia Research Institute, Sydney, NSW 2010, Australia.
Schizophr Res. 2015 Aug;166(1-3):212-8. doi: 10.1016/j.schres.2015.05.001. Epub 2015 Jun 2.
Metabotropic glutamate receptor 5 (mGluR5) is involved in hippocampal-dependent learning and memory, which are processes disrupted in schizophrenia. Recent evidence from human genetic and animal studies suggests that the regulation of mGluR5, including its interaction with trafficking molecules, may be altered in the disorder. However there have been no investigations of hippocampal mGluR5 or mGluR5 trafficking molecules in the postmortem schizophrenia brain to confirm this. In the present study, we investigated whether protein expression of mGluR5, as well as Norbin and Tamalin (modulators of mGluR5 signalling and trafficking), might be altered in the schizophrenia brain, using postmortem samples from the hippocampal CA1 region of schizophrenia subjects and matched controls (n=20/group). Protein levels of mGluR5 (total: 42%, p<0.001; monomer: 25%, p=0.011; dimer: 52%, p<0.001) and mGluR5 trafficking molecules (Norbin: 47%, p<0.001; Tamalin: 34%, p=0.009) were significantly higher in schizophrenia subjects compared to controls. To determine any influence of antipsychotic drug treatment, all proteins were also correlated with lifetime chlorpromazine equivalents in patients, and separately measured in the hippocampus of rats exposed to haloperidol or olanzapine treatment. mGluR5 was negatively correlated with lifetime antipsychotic drug exposure in schizophrenia patients, suggesting antipsychotic drugs could reduce mGluR5 protein in schizophrenia subjects. In contrast, mGluR5 and mGluR5 trafficking molecules were not altered in the hippocampus of antipsychotic drug treated rats. This investigation provides strong support for the hypothesis that mGluR5 is involved in the pathology of schizophrenia, and that alterations to mGluR5 trafficking might contribute to the hippocampal-dependent cognitive dysfunctions associated with this disorder.
代谢型谷氨酸受体5（mGluR5）参与海马体依赖的学习和记忆过程，而这些过程在精神分裂症中会受到破坏。来自人类遗传学和动物研究的最新证据表明，mGluR5的调节，包括其与转运分子的相互作用，在该疾病中可能会发生改变。然而，尚未有对精神分裂症患者死后大脑中的海马体mGluR5或mGluR5转运分子进行研究以证实这一点。在本研究中，我们使用精神分裂症患者海马体CA1区的死后样本和匹配的对照组（每组n = 20），调查了精神分裂症患者大脑中mGluR5以及Norbin和Tamalin（mGluR5信号传导和转运的调节剂）的蛋白质表达是否会发生改变。与对照组相比，精神分裂症患者中mGluR5的蛋白质水平（总量：42%，p < 0.001；单体：25%，p = 0.011；二聚体：52%，p < 0.001）和mGluR5转运分子（Norbin：47%，p < 0.001；Tamalin：34%，p = 0.009）显著更高。为了确定抗精神病药物治疗的任何影响，所有蛋白质还与患者的终生氯丙嗪等效剂量相关，并分别在接受氟哌啶醇或奥氮平治疗的大鼠海马体中进行测量。mGluR5与精神分裂症患者的终生抗精神病药物暴露呈负相关，表明抗精神病药物可以降低精神分裂症患者的mGluR5蛋白。相比之下，在接受抗精神病药物治疗的大鼠海马体中，mGluR5和mGluR5转运分子没有改变。这项研究为mGluR5参与精神分裂症病理学以及mGluR5转运改变可能导致与该疾病相关的海马体依赖的认知功能障碍这一假设提供了有力支持。
