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Epigenetic reprogramming of glutamate-mediated mTOR pathways in the anteroventral cingulate cortex of suicide victims
Suicide is an increasing public health problem, causing almost half of all violent deaths and resulting in almost one million fatalities in the world every year. It is of paramount importance to gain a comprehensive understanding of the brain mechanisms underlying the pathogenesis and pathophysiology of suicidal behavior, as well as to identify potential therapeutically relevant biomarkers in peripheral cells, in order to generate science-based, individually tailored protective and therapeutic interventions. We will address our working hypothesis that suicide may result from reduced neuronal activity and impaired synaptic plasticity, which constricts an individual´s competence to adequately and flexibly adapt to the environment. Besides specific genetic predispositions, evidence emerges that epigenetic mechanisms are also critically involved in the etiology of suicidal behavior. In postmortem human anterior cingulate cortex (from suicide victims and sudden-death controls archived in the Polish Suicide Brain Bank) the following hypotheses will be addressed: 1) is impaired neuronal activity in the suicidal brain associated with reduced rDNA transcriptional activity? 2) Is the reduced rDNA transcriptional activity caused by decreased mTOR expression, due to 3) reduced NMDA receptor expression/activation? 4) Is impaired synaptic plasticity associated with reduced synthesis of the synaptic plasticity protein Arc, as result of reduced mTOR expression? 5) Is the expected reduction in Arc expression related to long-term neuromorphological changes (dendrites, spine synapses)? 6) Is mTOR downregulation regulated via DNA hypermethylation? The added value of this project lies in the interdisciplinary and complementary experimental approaches, where different methodologies (AgNOR histology, mRNA expression/qPCR, DNA methylation analysis, 3D neuromorphology), are applied in tissue of the same individuals and thereby allows to correlate all biological parameters with each other and with the medical history of the individuals, and to create a multifaceted concept of the neurobiological changes in the suicidal brain.
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