title: Metabotropic glutamate receptor 5, and its trafficking molecules Norbin and Tamalin, are increased in the CA1 hippocampal region of subjects with schizophrenia.
abstract: 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.
authors.affiliation: 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. Electronic address: natalie_matosin@uow.edu.au.
authors.forename: Natalie
authors.initials: N
authors.lastname: Matosin
authors.affiliation: 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. Electronic address: fernande@uow.edu.au.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fernandez-Enright
authors.affiliation: 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. Electronic address: jsl934@uowmail.edu.au.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Lum
authors.affiliation: 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. Electronic address: ja393@uowmail.edu.au.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Andrews
authors.affiliation: 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. Electronic address: mengel@uow.edu.au.
authors.forename: Martin
authors.initials: M
authors.lastname: Engel
authors.affiliation: 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. Electronic address: xhuang@uow.edu.au.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
authors.affiliation: 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. Electronic address: knewell@uow.edu.au.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Newell
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002746:Chlorpromazine / Q000627:therapeutic use; D019281:Dimerization; D005260:Female; D006220:Haloperidol / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D000077152:Olanzapine; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D002352:Carrier Proteins; C574553:GRASP protein, rat; C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D008565:Membrane Proteins; C122108:NCDN protein, human; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D064529:Receptor, Metabotropic Glutamate 5; C109587:norbin; C410230:tamalin protein, human; D001569:Benzodiazepines; D006220:Haloperidol; D000077152:Olanzapine; D002746:Chlorpromazine
keywords: Hippocampus; Norbin; Schizophrenia; Tamalin; Trafficking; mGluR5