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Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors

Molecular Psychiatry volume 16, pages 533–547 (2011)Cite this article

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Abstract

Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocampal neurogenesis, its regulation by antidepressants, and its behavioral consequences. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed in the CNS, where its function is unknown. Here, we show, for the first time, the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1) approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety- and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supporting a pivotal function for MIF in both basal and antidepressant-stimulated adult hippocampal cell proliferation. Moreover, loss of MIF results in a behavioral phenotype that, to a large extent, corresponds with alterations predicted to arise from reduced hippocampal neurogenesis. These findings underscore MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition.

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Acknowledgements

This work was supported by grants from the EU 6th (FP6-2003-LIFESCIHEALTH-II-512012; PROMEMORIA) and 7th (FP7- HEALTH-F2M-2007-201600; MemStick) FP, and from the Swiss National Science Foundation (3100A0-108102) to CS. We thank Coralie Siegmund, Angelique Vaucher, Gregoire Parchet, Clara Rossetti, Alex Procter, and Samuel Hernández for technical assistance, Didier Le Roy for help with the MIF−/− transgenic mice, and Loay Awad for synthesizing Iso-1.

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  1. E Varea

    Present address: 5Current address: Department of Cell Biology and Parasitology, University of Valencia, Spain.,

  2. L Conboy and E Varea: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Behavioral Genetics, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland

    L Conboy, E Varea, J E Castro & C Sandi

  2. Laboratory of Molecular Neurobiology and Functional Neuroproteomics, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland

    H Sakouhi-Ouertatani & H A Lashuel

  3. Department of Medicine, Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland

    T Calandra

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Correspondence to C Sandi.

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Conboy, L., Varea, E., Castro, J. et al. Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors. Mol Psychiatry 16, 533–547 (2011). https://doi.org/10.1038/mp.2010.15

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