title: Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation.
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.
authors.affiliation: Faculty of Science, Medicine and Health, University of Wollongong, Northfields Ave, Wollongong, NSW, 2522, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Matosin
authors.forename: Francesca
authors.initials: F
authors.lastname: Fernandez-Enright
authors.forename: Samantha Jane
authors.initials: SJ
authors.lastname: Fung
authors.forename: Jeremy Stephen
authors.initials: JS
authors.lastname: Lum
authors.forename: Martin
authors.initials: M
authors.lastname: Engel
authors.forename: Jessica Lee
authors.initials: JL
authors.lastname: Andrews
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.forename: Cynthia Shannon
authors.initials: CS
authors.lastname: Weickert
authors.forename: Kelly Anne
authors.initials: KA
authors.lastname: Newell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D002352:Carrier Proteins; C539678:FRMPD4 protein, human; C576234:FRMPD4 protein, rat; C574553:GRASP protein, rat; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C122108:NCDN protein, human; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; C109587:norbin; C410230:tamalin protein, human