Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia

Abstract

To determine if NMDA receptor alterations are present in the cerebellum in schizophrenia, we measured NMDA receptor binding and gene expression of the NMDA receptor subunits in a post-mortem study of elderly patients with schizophrenia and non-affected subjects. Furthermore, we assessed influence of genetic variation in the candidate gene neuregulin-1 (NRG1) on the expression of the NMDA receptor in an exploratory study. Post-mortem samples from the cerebellar cortex of ten schizophrenic patients were compared with nine normal subjects. We investigated NMDA receptor binding by receptor autoradiography and gene expression of the NMDA receptor subunits NR1, NR2A, NR2B, NR2C and NR2D by in situ hybridization. For the genetic study, we genotyped the NRG1 polymorphism rs35753505 (SNP8NRG221533). Additionally, we treated rats with the antipsychotics haloperidol or clozapine and assessed cerebellar NMDA receptor binding and gene expression of subunits to examine the effects of antipsychotic treatment. Gene expression of the NR2D subunit was increased in the right cerebellum of schizophrenic patients compared to controls. Individuals carrying at least one C allele of rs35753505 (SNP8NRG221533) showed decreased expression of the NR2C subunit in the right cerebellum, compared to individuals homozygous for the T allele. Correlation with medication parameters and the animal model revealed no treatment effects. In conclusion, increased NR2D expression results in a hyperexcitable NMDA receptor suggesting an adaptive effect due to receptor hypofunction. The decreased NR2C expression in NRG1 risk variant may cause a deficit in NMDA receptor function. This supports the hypothesis of an abnormal glutamatergic neurotransmission in the right cerebellum in the pathophysiology of schizophrenia.

Reciprocal signalling between NR2 subunits of the NMDA receptor and neuregulin1 and their role in schizophrenia

“…Adding further complications to the regional specificity of NRG1 signalling, NR2C mRNA expression has been found to be decreased in a population of schizophrenia patients with a NRG1 polymorphism in the cerebellar molecular layer of the right hemisphere and vermis (Schmitt et al, 2010). Supporting this finding, the NRG1-β isoform has been shown to upregulate the expression of NR2C mRNA in cultured cerebellar slices (Ozaki et al, 1997).…”

Gene expression of glutamate transporters SLC1A1, SLC1A3 and SLC1A6 in the cerebellar subregions of elderly schizophrenia patients and effects of antipsychotic treatment

“…We have reported that individuals carrying at least one C allele of the NRG1 SNP rs35753505 (SNP8NRG221533) showed decreased expression of the GRIN2C (NR2C) subunit of the NMDA receptor in the right cerebellum, compared to individuals homozygous for the T allele. These results suggest that this SNP contributes to a glutamatergic hypofunction (Schmitt et al 2010). This variant forms part of the previously reported risk haplotype for schizophrenia, and has been described as a tagging SNP of the core at-risk haplotype (Stefansson et al 2002).…”

“…For each patient the history of antipsychotic treatment was assessed by examining the medical charts. Subjects ' last dose as well as the cumulative dose during the last 10 years of antipsychotic medication was calculated in chlorpromazine equivalents (CPE) according to Schmitt et al (2010). In all cases autopsy consent had been obtained from either the donor himself or a family member.…”

Die Glutamathypothese der Schizophrenie

“…Schließlich konnte in Post-mortem-Untersuchungen des Hippocampus bei Patienten mit einer Schizophrenie eine Reduktion der mRNALevel für den NMDAR-Rezeptor 1 nachgewiesen werden [41,42]. Im Cerebellum, das eine wichtige Rolle bei kognitiven Defiziten schizophrener Patienten spielt [43], wurde neben einer verän-derten Genexpression der NMDA-Rezeptor-Untereinheit NR2 D und funktionell bedeutender Glutamattransporter bei schizophrenen Patienten ein Zusammenhang zwischen der Expression der NR2C-Untereinheit und einem Risikogen für Schizophrenie, dem Neuregulin 1, (NRG1) gezeigt [44,45]. In mehreren Arbeiten wurde repliziert, dass Patienten mit einer Schizophrenie vermehrt Risikopolymorphismen bestimmter Gentranskripte (z.…”