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The BDNF hypothesis of depression: a new framework for understanding depression and the actions of antidepressant drugs

Tildelt: kr 3,3 mill.

Despite decades of research, the biological basis of major depression remains to be fully elucidated. Although antidepressants, such as serotonin reuptake inhibitors, rapidly increase serotonin levels in the extracellular space, the therapeutic effects of the drug are delayed by several weeks. This long delay constitutes a serious health problem due to the heightened risk of suicide and the loss of patient compliance. Understanding this delayed clinical response is therefore key to understanding depre ssion and a road to better treatment and management. Recently a new theory has been offered that might explain the delayed therapeutic effect of antidepressants and the pathogenesis of depression. The core idea is that chronic, but not acute, antidep ressant treatment leads to elevated synthesis of brain-derived neurotrophic (BDNF). Depression, in turn, is associated with decreased expression of BDNF in the hippocampus and other brain structures. In this way, the delayed therapeutic effects of antid epressants may depend on the delayed synthesis and subsequent effects of BDNF. Despite these correlations, there is still no evidence for a causal relationship between BDNF signalling, depression, and the effects of antidepressants. BDNF is a versat ile molecule implicated in diverse functions such as synaptic plasticity, neurogenesis, and survival. The aim of this study is to determine the physiological and molecular consequences of modified BDNF production in response chronic anti-depressant treatment and animal models of depression. Specifically, we will: 1) Define a causal role for BDNF signaling in response to antidepressant drugs and stress-induced depression. 2) Identify the impact of altered BDNF synthesis on synaptic plasticity, n eurogenesis, and neuronal survival. 3) Elucidate signal transduction pathways and gene effectors regulated by BDNF in response to treatment with antidepressant drugs and stress-induced depression.


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