Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation

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• 作者：Natalie Matosin ; Francesca Fernandez-Enright ; Samantha Jane Fung…
• 关键词：Metabotropic glutamate receptor ; GRM5 ; Immunoblot ; Human brain ; Schizophrenia ; Antipsychotic
• 刊名：Acta Neuropathologica
• 出版年：2015
• 出版时间：July 2015
• 年：2015
• 卷：130
• 期：1
• 页码：119-129
• 全文大小：1,917 KB
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• 作者单位：Natalie Matosin (1) (3) (4)
  Francesca Fernandez-Enright (1) (2) (3) (4)
  Samantha Jane Fung (4) (5) (6)
  Jeremy Stephen Lum (1) (3) (4)
  Martin Engel (1) (3) (4)
  Jessica Lee Andrews (1) (3) (4)
  Xu-Feng Huang (1) (3) (4)
  Cynthia Shannon Weickert (4) (5) (6)
  Kelly Anne Newell (1) (3) (4)
  
  1. Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, NSW, 2522, Australia
  3. Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia
  4. Schizophrenia Research Institute, Sydney, NSW, Australia
  2. Faculty of Social Sciences, University of Wollongong, Wollongong, NSW, Australia
  5. Neuroscience Research Australia, Randwick, NSW, Australia
  6. School of Psychiatry, University of New South Wales, Randwick, NSW, Australia
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Pathology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0533

文摘

Knockout of genes encoding metabotropic glutamate receptor 5 (mGluR5) or its endogenous regulators, such as Norbin, induce a schizophrenia-like phenotype in rodents, suggesting dysregulation of mGluR5 in schizophrenia. Human genetic and pharmacological animal studies support this hypothesis, but no studies have explored mGluR5 dysfunction at the molecular level in the postmortem schizophrenia brain. We assessed mGluR5 mRNA and protein levels in the dorsolateral prefrontal cortex (DLPFC) using a large cohort of schizophrenia and control subjects (n?=?37/group), and additionally measured protein levels of recently discovered mGluR5 endogenous regulators, Norbin (neurochondrin), Tamalin (GRASP-1), and Preso1 (FRMPD4), which regulate mGluR5 localization, internalization and signaling. While mGluR5 mRNA expression was unchanged, mGluR5 protein levels were significantly higher in schizophrenia subjects compared to controls (total: +22?%; dimer: +54?%; p?<?0.001). Conversely, mGluR5 regulatory proteins were expressed at lower levels in schizophrenia subjects compared to controls (Norbin ?7?%, p?<?0.001; Tamalin ?0?%, p?=?0.084; Preso1 ?9?%, p?=?0.001). mGluR5 protein was significantly associated with mGluR5 mRNA and mGluR5 endogenous regulators in control subjects, but these associations were lost in schizophrenia subjects. Lastly, there were no associations between protein measures and lifetime antipsychotic history in schizophrenia subjects. To confirm no antipsychotic influence, all proteins were measured in the prefrontal cortex of rats exposed to haloperidol or olanzapine; there were no effects of antipsychotic drug treatment on mGluR5, Norbin, Tamalin or Preso1. The results from our study provide compelling evidence that mGluR5 regulation is altered in schizophrenia, likely contributing to the altered glutamatergic signaling that is associated with the disorder.