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

Schmitt, A., Koschel, J., Zink, M., Bauer, M., Sommer, C., Frank, J., Treutlein, J., Schulze, T., Schneider-Axmann, T., Parlapani, E., Rietschel, M., Falkai, P., Henn, F. A. (March 2010) Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia. European Archives of Psychiatry and Clinical Neuroscience, 260 (2). pp. 101-11. ISSN 0940-1334 (Print)0940-1334 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/19856012
DOI: 10.1007/s00406-009-0017-1

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.

Item Type: Paper
Uncontrolled Keywords: Aged Animals Antipsychotic Agents/therapeutic use Autoradiography/methods Cerebellum/*metabolism Computational Biology/methods Disease Models, Animal Dizocilpine Maleate/pharmacokinetics Excitatory Amino Acid Antagonists/pharmacokinetics Female Gene Expression/*physiology Genotype Geriatric Assessment Humans Male Mice Middle Aged Online Systems Postmortem Changes Protein Binding/drug effects/physiology Protein Subunits/genetics/*metabolism Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate/genetics/*metabolism Schizophrenia/drug therapy/*pathology/physiopathology
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor
diseases & disorders > mental disorders > schizophrenia
organs, tissues, organelles, cell types and functions > tissues types and functions > cerebellum
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
CSHL Authors:
Communities: CSHL labs > Henn lab
Depositing User: Matt Covey
Date: March 2010
Date Deposited: 06 Jun 2014 19:15
Last Modified: 06 Jun 2014 19:15
PMCID: PMC2830629
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30269

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