Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation
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 −37 %, p < 0.001; Tamalin −30 %, p = 0.084; Preso1 −29 %, 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.
KeywordsMetabotropic glutamate receptor GRM5 Immunoblot Human brain Schizophrenia Antipsychotic
Postmortem brain tissues were received from the NSW Tissue Resource Centre, which is supported by the National Health and Medical Research Council of Australia, Schizophrenia Research Institute and the National Institute of Alcohol Abuse and Alcoholism [NIH (NIAA) R24AA012725]. The authors wish to thank the Schizophrenia Research Laboratory for preparation of the human brain tissue samples, Jiamei Lian, Hongqin Wang, Kiefer Zhang and Meng He for their assistance with the animal antipsychotic drug treatment and brain sampling, and Shan-Yuan Tsai for assistance with the qRT-PCR analyses. Cynthia Shannon Weickert was supported by the University of New South Wales, Neuroscience Research Australia and the Schizophrenia Research Institute (utilizing infrastructure funding from the NSW Ministry of Health and the Macquarie Group Foundation). Cynthia Shannon Weickert is a recipient of a National Health and Medical Research Council (Australia) Senior Research Fellowship (#1021970). This study was supported by the Schizophrenia Research Institute, utilizing infrastructure funding from the NSW Ministry of Health. The animal antipsychotic drug study was supported by a National Health and Medical Research Council grant to Xu-Feng Huang (Grant ID 635231). Natalie Matosin, Jeremy S. Lum and Jessica L. Andrews are supported by Ian Scott Scholarships from Australian Rotary Health.
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