Antidepressive effects of targeting ELK-1 signal transduction

Abstract

Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement1. In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted2,3,4. The extracellular signal–regulated kinase (ERK) pathway is implicated in mood regulation5,6,7, but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner8, as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.

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Fig. 1: Increased hippocampal ELK1 mRNA expression in depression.
Fig. 2: Reduction of blood ELK1 mRNA levels reflects antidepressant efficacy.
Fig. 3: Selective inhibition of p-ELK-1 reverses stress-induced behavioral, molecular and plasticity changes.
Fig. 4: ELK-1 overexpression in the hippocampus induces depressive-like behaviors.

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Acknowledgements

We thank P. Greengard, G. G. Nomikos and R. H. Perlis for critical reading of the manuscript. We want to acknowledge M. -J. Brisorgueil and A. Besnard for help with immunohistochemistry experiments, C. Tecker for qPCR experiments in mice, P. Vanhoutte for TDE design and the Imaging Platform at the Institut de la Vision (Paris, France) for slide scanning. This research was supported in part by ERA-NET NEURON (Grant WM2NA; N.M., C.M., E.T.T.), Labex-Biopsy (AIM: E.T.T.; SignAddict: J.C.), FRC (Fondation Recherche pour le Cerveau; E.T.T.), the National Hospital Clinical Research Program (Assistance Publique-Hopitaux de Marseille; PHRC no. 2010-19: R.B.), Conseil Régional d’Aquitaine (L.M., L.G.) and the Canadian Institute for Health Research (B.G. and G.T.). R.B. was supported by a FondaMental Servier postdoctoral fellowship, and K.A. was supported by an MRT (Ministère Recherche Technologie, Ecole Doctorale MTCI) graduate award. B.G. is the holder of the Graham Boeckh Chair, and E.T.T. is a past recipient of the Bodossakis Foundation Young Scientist Award.

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E.T.T. and B.G. designed the study with the help of V.G. and J.C. for mouse studies and R.B. and G.T. for clinical studies; K.A., S.F., V.G. and M.-A.E.K. performed experiments and analyzed data in mouse studies; R.M., A. Barbé, C.E.A.d.M., W.J., A. Bochereau, A.O., E.I., C.G., L.M., F.L., S.G., L.G. and V.V. performed experiments in mice; R.B., N.M. and G.T. contributed clinical and postmortem samples; R.B., J.P.L. and E.C.I. generated and analyzed clinical and postmortem data; E.M. and F.M. generated in vivo electrophysiological data; Y.C.T. and T.P.W. performed electrophysiological experiments; J.G., E.C.I. and C.M. performed qPCR experiments; S.D. and S.F.  performed FISH experiments; F.Y. designed and provided viral vectors; J.C. designed and provided pharmacological tools; E.T.T. also participated in analyses of behavioral and clinical data; V.G., R.B., J.G., E.C.I., N.M., F.M., B.G. and E.T.T. wrote the paper.

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Correspondence to Bruno Giros or Eleni T. Tzavara.

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Competing interests

The TDE peptide used in the present article and its application in depression are protected by the published patents WO 2006/087242 and WO2010/037841, respectively, filed in Europe, the United States, Canada and Japan. This does not alter our adherence to Nature Publishing Group policies on sharing data and materials. J.C., B.G. and E.T.T. are founding shareholders of Melkin Pharmaceuticals, a biotech company, which has developed the TDE peptide as a drug candidate. The company did not have any role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Apazoglou, K., Farley, S., Gorgievski, V. et al. Antidepressive effects of targeting ELK-1 signal transduction. Nat Med 24, 591–597 (2018). https://doi.org/10.1038/s41591-018-0011-0

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