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

Journal article


Matosin, Natalie, Fernandez-Enright, Francesca Elizabeth, Fung, Samantha Jane, Lum, Jeremy Stephen, Engel, Martin, Andrews, Jessica Lee, Huang, Xu-Feng, Weickert, Cynthia Shannon and Newell, Kelly Anne. (2015). Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: Towards a model of mGluR5 dysregulation. Acta Neuropathologica. 130(1), pp. 119 - 129. https://doi.org/10.1007/s00401-015-1411-6
AuthorsMatosin, Natalie, Fernandez-Enright, Francesca Elizabeth, Fung, Samantha Jane, Lum, Jeremy Stephen, Engel, Martin, Andrews, Jessica Lee, Huang, Xu-Feng, Weickert, Cynthia Shannon and Newell, Kelly Anne
Abstract

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
Year2015
JournalActa Neuropathologica
Journal citation130 (1), pp. 119 - 129
PublisherSpringer
ISSN1432-0533
Digital Object Identifier (DOI)https://doi.org/10.1007/s00401-015-1411-6
Page range119 - 129
Research GroupSchool of Behavioural and Health Sciences
Publisher's version
File Access Level
Controlled
Place of publicationGermany
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