J Psychiatry Neurosci 2012;37(4):267-72
Rebecca Lyddon, BS; Scott Navarrett, BS; Stella Dracheva, PhD
Lyddon, Navarrett, Dracheva — Department of Psychiatry, Mount Sinai School of Medicine, New York, NY; Navarrett, Dracheva — James J. Peters Veterans Affairs Medical Center, Bronx, NY
Background: Dysfunction of glutamate neurotransmission has been implicated in the pathology of schizophrenia and bipolar disorder, and one mechanism by which glutamate signalling can be altered is through RNA editing of ionotropic glutamate receptors (iGluRs). The objectives of the present study were to evaluate the editing status of iGluRs in the human prefrontal cortex, determine whether iGluR editing is associated with psychiatric disease or suicide and evaluate a potential association between editing and alternative splicing in the α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) iGluR subunits’ pre-mRNA.
Methods: We studied specimens derived from patients with antemortem diagnoses of bipolar disorder (n = 31) or schizophrenia (n = 34) who died by suicide or other causes, and from psychiatrically healthy controls (n = 34) who died from causes other than suicide. The RNA editing at all 8 editing sites within AMPA (GluA2–4 subunits) and kainate (GluK1–2 subunits) iGluRs was analyzed using a novel real-time quantitative polymerase chain reaction assay.
Results: No differences in editing were detected among schizophrenia, bipolar or control groups or between suicide completers and patients who died from causes other than suicide. The editing efficiency was significantly higher in the flop than in the flip splicoforms of GluA3-4 AMPA subunits (all p < 0.001). Limitations: The study is limited by the near absence of specimens from medicationnaive psychiatric patients and considerable variation in medication regimens among individuals, both of which introduce considerable uncertainty into the analysis of potential medication effects.
Conclusion: We found that iGluR RNA editing status was not associated with bipolar disorder, schizophrenia or suicide. Differences in editing between flip and flop splicoforms suggest that glutamate sensitivity of receptors containing GluA3 and/or GluA4 flop subunits is moderated as a result of increased editing.
Submitted Aug. 16, 2011; Revised Dec. 27, 2011, Jan. 11, 2012; Accepted Jan. 12, 2012.
Acknowledgments: This study was supported by the Department of Veterans Affairs (VA), Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, by a VA Merit award (S. Dracheva), NIMH/NIH grant MH090352 (S. Dracheva), a grant from the American Foundation for Suicide Prevention (S. Dracheva) and by the VISN3 Mental Illness Research and Education Clinical Center (S. Dracheva). Postmortem brain tissue was donated by The Stanley Medical Research Institute.
Competing interests: None declared for R. Lyddon and S. Navarrett. As above for S. Dracheva.
Contributors: R. Lyddon and S. Dracheva designed the study, analyzed the data and wrote the article. R. Lyddon and S. Navarrett acquired the data. All authors reviewed the article and approved its publication.
Correspondence to: S. Dracheva, Psychiatry Research (4F-02), Bronx VA Medical Center, 130 West Kingsbridge Rd., Bronx NY 10468; Stella.Dracheva@mssm.edu