Gene expression of NMDA receptor subunits in the cerebellum of elderly patients with schizophrenia.
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.
Schmitt
Andrea
A
Department of Psychiatry, University of Goettingen, von-Siebold Strasse 5, Göttingen, Germany. aschmit@gwdg.de
Koschel
Jiri
J
Zink
Mathias
M
Bauer
Manfred
M
Sommer
Clemens
C
Frank
Josef
J
Treutlein
Jens
J
Schulze
Thomas
T
Schneider-Axmann
Thomas
T
Parlapani
Eleni
E
Rietschel
Marcella
M
Falkai
Peter
P
Henn
Fritz A
FA
D000368:Aged; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001345:Autoradiography / Q000379:methods; D002531:Cerebellum / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D005838:Genotype; D015577:Geriatric Assessment; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009862:Online Systems; D011180:Postmortem Changes; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate