Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects

The extracellular regulated kinases (ERK) 1 and ERK2 are members of mitogen -activated protein (MAP) kinase family that play an important role in trans ducing extracellular signals to the nucleus and have been implicated in a b road spectrum of biological responses. To test the hypothesis that MAP kina ses may be involved in depression, we examined the activation of p44/42 MAP kinase and expression of ERK1 and ERK2 in the post-mortem brain tissue obt ained from non-psychiatric control subjects (n = 11) and age- and the post- mortem interval-matched depressed suicide subjects (n = 11). We observed th at p44/42 MAP kinase activity was significantly decreased in the prefrontal cortical areas (Brodmann's areas 8, 9 and 10) and the hippocampus of depre ssed suicide subjects without any change in the cerebellum. This decrease w as associated with a decrease in mRNA and protein levels of ERK1 and ERK2. In addition, the expression of MAP kinase phosphatase (MKP)P, a 'dual funct ion' ERK1/2 phosphatase, was increased in the prefrontal cortex and hippoca mpus. These studies suggest that p44/42 MAP kinases are less activated in t he post-mortem brain of depressed suicide subjects and this may be because of reduced expression of ERK1/2 and increased expression of MKP2. Given the role of MAP kinases in various physiological functions and gene expression , alterations in p44/42 MAP kinase activation and expression of ERK1/2 may contribute significantly to the pathophysiology of depressive disorders.