Antidepressive effects of targeting ELK-1 signal transduction. (May 2018)

• Record Type: Journal Article
• Authors: Apazoglou, Kallia; Farley, Séverine; Gorgievski, Victor; Belzeaux, Raoul; Lopez, Juan; Grenier, Julien; Ibrahim, El; El Khoury, Marie-Anne; Tse, Yiu; Mongredien, Raphaele; Barbé, Alexandre; Macedo, Carlos; Jaworski, Wojciech; Bochereau, Ariane; Orrico, Alejandro; Isingrini, Elsa; Guinaudie, Chloé; Mikasova, Lenka; Louis, Franck; Gautron, Sophie; Groc, Laurent; Massaad, Charbel; Yildirim, Ferah; Vialou, Vincent; Dumas, Sylvie; Marti, Fabio; Mechawar, Naguib; Morice, Elise; Wong, Tak; Caboche, Jocelyne; Turecki, Gustavo; Giros, Bruno; Tzavara, Eleni;
• Is Part Of: Nature medicine. Volume 24:Number 5(2018)
• Page Start: 591
• Page End: 597
• Publication Date: 2018-05
• Subjects: Pathology, Molecular -- Periodicals; Molecular biology -- Periodicals; 610.724
• DOI: 10.1038/s41591-018-0011-0
• Languages: English
• ISSNs: 1078-8956

Abstract

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 warranted2–4 . The extracellular signal–regulated kinase (ERK) pathway is implicated in mood regulation5–7, 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 reduceELK1 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. The transcription factor ELK-1 is upregulated in patients with major depressive disorder, and selective inhibition of hippocampal ELK-1 produces rapid antidepressive effects in rodent models of depression.