MAP Kinase negative regulator [MKP-1] is a possible target for antidepressants

A PROTEIN involved in the growth and development of brain cells could play a role in depression and provide a possible target for antidepressants.

Ron Duman and colleagues at Yale University began their search for a mechanism behind depression by comparing post-mortem brain samples from 21 people who had been depressed and 18 people of the same age.

The group looked for differences in gene expression by comparing levels of messenger RNA – the middle-man between gene and protein production – throughout the entire genome.

While Duman’s team found several hundred differences, most striking were levels of mRNA for a particular protein, MKP-1, which inhibits a pathway involved in neural growth and development. The brains of people with depression contained twice the amount of other people.

When the group over-expressed the gene for MKP-1 in the brains of healthy rats, the animals began to show signs of depression which disappeared when treated with an antidepressant (Nature Medicine, DOI: 10.1038/nm.2219).

“[The findings] suggest a novel target for drug development,” says Steven Garlow at Emory University in Atlanta, Georgia.

Nature Medicine
Published online: 17 October 2010 | doi:10.1038/nm.2219

A negative regulator of MAP kinase causes depressive behavior

Vanja Duric1, Mounira Banasr1, Pawel Licznerski1, Heath D Schmidt1, Craig A Stockmeier2,3, Arthur A Simen1, Samuel S Newton1 & Ronald S Duman1

Abstract

The lifetime prevalence (~16%)1 and the economic burden ($100 billion annually)2, 3 associated with major depressive disorder (MDD) make it one of the most common and debilitating neurobiological illnesses. To date, the exact cellular and molecular mechanisms underlying the pathophysiology of MDD have not been identified. Here we use whole-genome expression profiling of postmortem tissue and show significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1, encoded by DUSP1, but hereafter called MKP-1) in the hippocampal subfields of subjects with MDD compared to matched controls. MKP-1, also known as dual-specificity phosphatase-1 (DUSP1), is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade4, a major signaling pathway involved in neuronal plasticity, function and survival5, 6. We tested the role of altered MKP-1 expression in rat and mouse models of depression and found that increased hippocampal MKP-1 expression, as a result of stress or viral-mediated gene transfer, causes depressive behaviors. Conversely, chronic antidepressant treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress. These postmortem and preclinical studies identify MKP-1 as a key factor in MDD pathophysiology and as a new target for therapeutic interventions.

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