A negative regulator of MAP kinase causes depressive behavior

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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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Figure 1: MKP-1 is dysregulated in major depressive disorder (MDD).
Figure 2: Influence of CUS and antidepressant treatment on behavior and MKP-1 expression.
Figure 3: Influence of MKP-1 overexpression on behavior in rodent models of depression.
Figure 4: Influence of MKP-1 deletion on behavioral models of depression.

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Acknowledgements

This work is supported by US Public Health Service grants MH45481 (R.S.D.), 2 P01 MH25642 (R.S.D.), MH67996 (C.A.S.) and P20 RR17701 (C.A.S.) and the Connecticut Mental Health Center (R.S.D.). We acknowledge the invaluable contributions made by the families consenting to donate brain tissue and be interviewed. We also thank the Cuyahoga County Coroner and staff for their willing assistance. We are grateful for the contributions of J. Overholser, G. Jurjus, H. Meltzer, L. Konick, L. Dieter, N. Herbst, G. Mahajan, H. Kooiman and J. Cobb in the psychiatric assessment and human tissue dissection and preparation. We also thank R. Terwilliger and H.J. Kang for technical assistance with gene expression analysis, A. Bennett (Yale University School of Medicine) for Mkp-1−/− mice, X.Y. Li for assistance in breeding and genotyping Mkp-1−/− mice and R. DiLeone (Yale University School of Medicine) for generously donating AAV-CMV-GFP plasmid used to generate recombinant AAVs.

Author information

V.D. prepared the original draft of the manuscript and was involved in all aspects of the experimental design and research, including execution of all microarray and molecular experiments, as well as behavioral tests in rats and mice. M.B. conducted the behavioral aspects of the rat CUS study, assisted with rat surgeries and was involved in analysis and interpretation of behavioral tests. P.L. was responsible for optimization, construction and preparation of recombinant AAVs. H.D.S. conducted baseline behavior tests in Mkp-1−/− mice. C.A.S. was responsible for human tissue generation and preparation of relevant human subjects' information tables and methodology. A.A.S. conducted statistical analysis of microarray experiments. S.S.N. assisted in the development and optimization of microarray experiments. R.S.D. was involved in all aspects of study design, data analysis, interpretation of results and preparation of the manuscript and figures. All authors discussed the results presented in the manuscript.

Correspondence to Ronald S Duman.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Supplementary Tables 1–6 and Supplementary Methods (PDF 1425 kb)

Supplementary Data 1

Dysregulated genes in dentate gyrus (XLS 1655 kb)

Supplementary Data 2

Dysregulated genes in CA1 (XLS 504 kb)

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Duric, V., Banasr, M., Licznerski, P. et al. A negative regulator of MAP kinase causes depressive behavior. Nat Med 16, 1328–1332 (2010) doi:10.1038/nm.2219

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