Alternative Splicing, Methylation State, and Expression Profile of Tropomyosin-Related Kinase B in the Frontal Cortex of Suicide Completers

Abstract

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.

Functional DNA methylation in a transcript specific 3′UTR region of TrkB associates with suicide

“…Previous studies had shown differences in DNA methylation 9 and histone modifications 5 in the TrkB promoter and microRNA binding 10 in TrkB-T1 3′UTR sequences between controls and suicide completers. However, the results from these previous studies suggested that additional mechanisms were necessary to explain the extreme decrease in TrkB-T1 expression observed in frontal cortical areas of suicide completers.…”

“…8 Previous studies point to a change in the level of TrkB expression in suicide completers. [9][10][11] The TrkB gene, located on chromosome 9, encodes three receptors of neurotrophins, characterized by specific 3′UTR sequences. TrkB gene products are involved in neurotransmission, calcium release, synaptic plasticity, and cell survival, 12 processes whose altered functions have been implicated in the neurobiology of suicide.…”

“…13 Downregulation of this truncated TrkB transcript, in coordination with a network of several other astrocytic genes, 14 has been reported in several brain regions of suicide completers. 9 Interestingly, convergent evidence from studies investigating gene expression patterns 15 to studies focusing on cell morphology, 16 has been increasingly suggesting that astrocyte dysregulation plays an important role in depression and suicide.…”

“…Studies of DNA methylation in the TrkB promoter sequence in cortical tissue from that brain region, and of microRNA binding in the 3′UTR sequence suggested that these marks could be partially responsible for the regulation of TrkB-T1 expression. 9,10 However, DNA methylation in promoter sequence and the functional effect of microRNA binding described in the 3′UTR sequence, whether individually or combined, seem not to be sufficient to explain the large and specific decrease of TrkB-T1 transcript levels associated with suicide. Other mechanisms could be involved in that transcript specific regulation.…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Decreased astrocyte mRNA and/or protein expression of GFAP (Braun et al, 2009), aquaporin 4 (Rajkowska and Stockmeier, 2013), connexins (Miguel-Hidalgo et al, 2014;Rajkowska and Stockmeier, 2013;Verkhratsky et al, 2015b), plasmalemmal glutamate transporters (Bernard et al, 2011;Ernst et al, 2009), and glutamine synthetase (Barley et al, 2009;Bernard et al, 2011;Rajkowska et al, 1999;Sequeira et al, 2009) in postmortem brain samples from depressed suicides. Evidence of astroglial dysfunction and immune activation in postmortem brain samples from depressed suicide victims (Nagy et al, 2015;Torres-Platas et al, 2014a;TorresPlatas et al, 2011).…”