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

Andrea Schmitt, Jiri Koschel, Mathias Zink, Manfred Bauer, Clemens Sommer, Josef Frank, Jens Treutlein, Thomas Schulze, Thomas Schneider-Axmann, Eleni Parlapani, Marcella Rietschel, Peter Falkai, Fritz A. Henn

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)101-111
Number of pages11
JournalEuropean Archives of Psychiatry and Clinical Neuroscience
Volume260
Issue number2
DOIs
StatePublished - Mar 2010
Externally publishedYes

Keywords

  • Antipsychotics
  • Cerebellum
  • Gene expression
  • Neuregulin-1
  • NMDA receptor binding
  • NMDA receptor subunits
  • Schizophrenia

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry
  • Pharmacology (medical)

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  • Cite this

    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. (2010). Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia. European Archives of Psychiatry and Clinical Neuroscience, 260(2), 101-111. https://doi.org/10.1007/s00406-009-0017-1