Depression is a debilitating neuropsychiatric disorder that affects ~17% of the US population at some point in their lives (Kessler et al., 2003). Currently approved medications can require several weeks to achieve efficacy and many patients never achieve complete remission of depressive symptoms. It is therefore critical to better understand the underlying causes of depression and identify novel treatment strategies that can improve patient outcome. It is thought that depression may be caused, at least in part, by exposure to chronic stress. Chronic stress has detrimental effects on the morphology and function of neurons in the prefrontal cortex and hippocampus. Recent evidence has identified that the drug ketamine produces rapid and robust effects in depressed patients (Berman et al., 2000;Zarate et al., 2006) and studies in rodents have found that these robust effects are due to activation of a cell signaling pathway involving mTOR and p70 S6 kinase, which is required for the antidepressant response (Li et al., 2010). Activation of these signaling pathways leads to increased excitatory synapses in the prefrontal cortex and reverses the negative effects of stress on these synapses (Li et al., 2011). The project proposed here aims to determine if increasing the activity p70 S6 kinase alone is sufficient to produce antidepressant effects and increase resilience to the behavioral and neuronal insults produced by exposure to chronic stress. This will be achieved by using a viral vector to deliver a mutant, constitutively active version of p70 S6 kinase to the prefrontal cortex or hippocampus of rats before exposure to chronic stress. Following viral expression, rats will be exposed to chronic stress and assessed for behavioral deficits and neuronal atrophy produced by stress. It is anticipated that increasing the activity of the p70 S6 kinase pathway will prevent depressive-like behavior in rats and protect neurons from the deleterious effects of stress. The data obtained here will provide important insight into molecular events that underlie stress resilience and can help identify and elucidate novel pathways and treatment strategies for depression.
Major Depressive Disorder (MDD) is a prevalent mental illness that impacts the lives of roughly 17% of the US population at some point in their lives and can have devastating personal and societal costs. Currently available treatments for depression are effective in only a subset of patients and can require weeks of treatment to achieve minimal efficacy. The proposed project will provide important insight into the molecular mechanisms that mediate resilience to stress and antidepressant response and will guide development of novel therapeutics for depression with more robust and rapid- acting effects.
|Dwyer, Jason M; Maldonado-Avilés, Jaime G; Lepack, Ashley E et al. (2015) Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior. Proc Natl Acad Sci U S A 112:6188-93|