Alternative splicing, methylation state, and expression profile of tropomyosin-related kinase B in the frontal cortex of suicide completers.
BACKGROUND
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.


METHODS
Postmortem case-control study. Patients, Setting, and


METHODS
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.


CONCLUSIONS
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.
Ernst
Carl
C
Departments ofNeurology and Neurosurgery, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.
Deleva
Vesselina
V
Deng
Xiaoming
X
Sequeira
Adolfo
A
Pomarenski
Amanda
A
Klempan
Tim
T
Ernst
Neil
N
Quirion
Remi
R
Gratton
Alain
A
Szyf
Moshe
M
Turecki
Gustavo
G
D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics*; D001253:Astrocytes / Q000473:pathology; D015153:Blotting, Western; D002531:Cerebellum / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D005625:Frontal Lobe / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms; D020813:Receptor, trkB / Q000235:genetics*; D013405:Suicide / Q000523:psychology*
D020033:Protein Isoforms; D020813:Receptor, trkB