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Alternative Splicing, Methylation State, and Expression Profile of Tropomyosin-Related Kinase B in the Frontal Cortex of Suicide Completers
Carl Ernst, MSc;
Vesselina Deleva, MSc;
Xiaoming Deng, MD;
Adolfo Sequeira, PhD;
Amanda Pomarenski, BSc;
Tim Klempan, PhD;
Neil Ernst, MSc;
Remi Quirion, PhD;
Alain Gratton, PhD;
Moshe Szyf, PhD;
Gustavo Turecki, MD, PhD
Arch Gen Psychiatry. 2009;66(1):22-32.
Context Although most of the effort to understand the neurobiology of depressive states and suicide has focused on neuronal processes, recent studies suggest that astroglial dysfunction may play an important role. A truncated variant of the tropomyosin-related kinase B (TrkB.T1) is expressed in astrocytes, and brain-derived neurotrophic factor–TrkB signaling has been linked to mood disorders.
Objective To test the hypothesis that TrkB.T1 expression is downregulated in suicide completers and that this downregulation is mediated by an epigenetic process.
Design Postmortem case-control study.
Patients, Setting, and Main Outcome Measures Thirty-nine French Canadian men underwent screening at the Douglas Hospital Research Institute using the HG-U133 plus 2 microarray chip. Nine frontal cortical regions and the cerebellum were assessed using a microarray screening approach for extreme expression differences across subjects and a conventional screening approach. Results were validated by quantitative polymerase chain reaction and Western blot analyses. Animal experiments were performed to control for drug and alcohol effects. Genetic and epigenetic studies were performed by means of direct sequencing and bisulfite mapping.
Results We found that 10 of 28 suicide completers (36%) demonstrated significant decreases in different probe sets specific to TrkB.T1 in Brodmann areas 8 and 9. These findings were generalizable to other frontal regions but not to the cerebellum. The decrease in TrkB expression was specific to the T1 splice variant. Our results were not accounted for by substance comorbidity or by reduction in astrocyte number. We found no effect of genetic variation in a 2500–base pair promoter region or at relevant splice junctions; however, we detected an effect of methylation state at particular CpG dinucleotides on TrkB.T1 expression.
Conclusion A reduction of TrkB.T1 expression in the frontal cortex of a subpopulation of suicide completers is associated with the methylation state of the promoter region.
Author Affiliations: McGill Group for Suicide Studies (Mr C. Ernst, Ms Deleva, and Drs Deng, Sequeira, Klempan, and Turecki) and Departments of Neurology and Neurosurgery (Mr C. Ernst, Ms Pomarenski, and Drs Klempan, Quirion, Gratton, and Turecki), Psychiatry (Drs Quirion, Gratton, and Turecki), and Pharmacology and Therapeutics (Dr Szyf), McGill University, and Department of Psychiatry, Douglas Hospital Research Institute (Dr Turecki), Montreal, Quebec, Canada; and Department of Computer Science, University of Toronto, Toronto, Ontario, Canada (Mr N. Ernst).
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