Gene expression of NMDA receptor subunits in the c

Authors: Andrea Schmitt Jiri Koschel Mathias Zink Manfred Bauer Clemens Sommer Josef Frank Jens Treutlein Thomas Schulze Thomas SchneiderAxmann Eleni Parlapani Marcella Rietschel Peter Falkai Fritz A Henn

Publish Date: 2009/05/12

Volume: 260, Issue: 2, Pages: 101-111

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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 postmortem study of elderly patients with schizophrenia and nonaffected subjects Furthermore we assessed influence of genetic variation in the candidate gene neuregulin1 NRG1 on the expression of the NMDA receptor in an exploratory study Postmortem 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 schizophreniaThe cerebellum is known to be involved in motor control but positron emission tomography PET and functional magnetic resonance imaging fMRI studies have also shown the involvement of the cerebellum in different cognitive tasks 2 51 During the last decades the cerebellum has been implicated in the pathophysiology of schizophrenia with the corticothalamocerebellar circuit receiving particular attention 4 Evidence from PET as well as structural and functional MRI studies has shown decreased volumes of the total cerebellum left cerebellar hemisphere and right vermis 60 as well as correlation of the volume reduction with psychopathological subscores 26 43 This has raised questions concerning the underlying biological dysfunction 1Hspectroscopic MRI studies have revealed decreased Nacetylaspartate NAA and creatine in the anterior vermis and cortex pointing to altered neuronal integrity 12 17 Reductions of NAA indicate a loss of functional and structural integrity of neurons dendrites and axons Such neuronal dysfunctions may involve a glutamatergic deficit in cerebellar subregions of schizophrenic patientsThe glutamate hypothesis of schizophrenia is based on the observation that phencyclidine and ketamine which block the ion channel of the glutamatergic Nmethyldaspartate NMDA receptor initiate an NMDA receptor hypofunction and precipitate psychosis 29 30 resulting in a final hypoglutamatergic state of corticostriatal projections 18 44 The NMDA receptor is composed of different subunits responsible for various functional properties 27 39 The obligate NR1 subunit combines two or three NR2 subunits NR2A NR2B NR2C and NR2D to form the functional receptorStudies using brain tissue obtained from postmortem have examined the expression of glutamate receptor subunits and support the hypothesis of a glutamate dysfunction in schizophrenia In contrast to neocortical brain regions molecular investigations of the cerebellum are sparse concerning schizophrenia In cerebellar Purkinje and Golgi neurons all NMDA receptor subunits are expressed 10 52 and may be altered in schizophrenia However one study investigating only the left cerebellar granule cell layer showed no difference in gene expression of NMDA receptor subunits compared to healthy controls 1 The expression of the NR2C subunit has been reported to be regulated by neuregulin1 in maturing synapses of the cerebellar granule cells 47 Several studies suggest NRG1 as a vulnerability gene for schizophrenia 23 The mechanisms that might underlie the contribution of NRG1 risk haplotypes to disease pathophysiology however remain elusive Particularly the influence of NRG1 risk variants on the expression of subunits of the NMDA receptor is unknownThe present study sought to determine whether the expression of genes encoding for NR1 NR2A NR2B NR2C and NR2D subunits of the NMDA receptor or NMDA receptor binding are specifically altered in the cerebellum For additional investigation of a possible influence of NRG1 genotype variation on the expression of the NR2C subunit we genotyped the samples for the NRG1 polymorphism rs35753505 SNP8NRG221533 This variant forms part of the previously reported risk haplotype for schizophrenia and has been described as a tagging SNP of the core atrisk haplotype 23 As all schizophrenic patients in our study had been on antipsychotic medication over long periods of time medication effects have to be included as a possible influential factor Accordingly we conducted an additional animal study closely investigating the effects of a typical haloperidol and an atypical clozapine antipsychotic medication on NMDA receptor binding and gene expression of subunits of the NMDA receptor in different cerebellar rat brain regions after drug administration for up to 6 months

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