CDK5-DA signaling has a key role in depressive like behaviours manifested at early disease stage in HD

Abstract

Depression is one of the most common psychiatric symptoms in Huntington¿s disease (HD), estimated to occur in between 20 and 50 % of HD carriers. Notably, mood disturbances may precede the onset of cognitive changes and motor disturbances by several years making depression one of the earliest symptoms in HD. Several evidences indicate that depressive symptoms appear in the early stages of the disease and can prevail throughout the clinical course with devastating consequences as they may exacerbate cognitive and motor symptoms. Studies about the biochemical, molecular and cellular bases involved in the pathophysiology of depression in HD are scarce. Several evidences have shown that both anxiety and depression could be regulated by the activity of Cdk5, a multifunctional kinase involved in a wide range of neuronal functions from synaptic plasticity to cell survival. Increases in the activity of this kinase has been associated with altered neuronal processes, cell death and dysfunction characteristic of different neuropsychiatric and neurodegenerative diseases. Therefore we hypothesize that aberrant activation of Cdk5 could be involved in the depressive symptoms charateristics of the early stages of HD. In this study we demonstrated that our HD KI mice dysplayed depressive-like behaviors without an anxiety component starting at 2 months of age and preceeding cognitive deficits (4-6 months of age and motor impairments (8 months of age) by several months. This early depressive behavior was associated with alterations in the dopaminergic and seratoninergic metabolism. Importantly, in this study we used genetic and pharmacological approaches to define whether Cdk5 is a good drug target for early treatment of depressive symptoms in HD. Our results demonstrate that cdk5 play a critical rol in the development of depressive like-behaviors by modulation of dopamine signaling.