| 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. |
| Abstract | The neurotransmitter disturbances responsible for cognitive dysfunction in schizophrenia are hypothesized to originate with alterations in postsynaptic scaffold proteins. We have recently reported that protein levels of FRMPD4, a multiscaffolding protein that modulates both Homer1 and postsynaptic density protein 95 activity, is altered in the schizophrenia postmortem brain, in regions involved in cognition. Here, we set out to investigate whether genetic variation in FRMPD4 is associated with cognitive function in people with schizophrenia. We selected and examined a novel single nucleotide polymorphism, rs5979717 (positioned in the noncoding 3' untranslated region of FRMPD4 and potentially influencing protein expression), for its association with schizophrenia and nine measures of cognitive function, using age-matched and sex-matched samples from 268 schizophrenia cases and 268 healthy controls. Brain samples from 20 schizophrenia patients and 20 healthy controls were additionally genotyped to study the influence of this variant on protein expression of FRMPD4. Allelic distribution of rs5979717 was associated with schizophrenia in females (?=4.52, P=0.030). No effects of rs5979717 were observed on cognitive performance, nor an influence of rs5979717 genotypes on the expression of FRMPD4 proteins in postmortem brain samples. These data provide initial support for a sex-specific role for common variation in rs5979717 in schizophrenia, which now warrants further investigation. |