• DOI:10.1038/s41591-018-0011-0
• Corpus ID: 13663321

Antidepressive effects of targeting ELK-1 signal transduction

@article{Apazoglou2018AntidepressiveEO,
  title={Antidepressive effects of targeting ELK-1 signal transduction},
  author={Kallia Apazoglou and S{\'e}verine Farley and Victor Gorgievski and Raoul Belzeaux and Juan Pablo Lopez and Julien Grenier and El Ch{\'e}rif Ibrahim and Marie-Anne El Khoury and Yiu Chung Tse and Rapha{\"e}le Mongr{\'e}dien and Alexandre Barb{\'e} and Carlos E. A. de Macedo and Wojciech Jaworski and Ariane Bochereau and Alejandro Orrico and Elsa Isingrini and Chlo{\'e} Guinaudie and Lenka Mikasov{\'a} and Franck Louis and Sophie Gautron and Laurent Groc and Charbel Massaad and Ferah Yildirim and Vincent Vialou and Sylvie Dumas and Fabio Marti and Naguib Mechawar and Elise Morice and Tak Pan Wong and Jocelyne Caboche and Gustavo Turecki and Bruno Giros and Eleni T. Tzavara},
  journal={Nature Medicine},
  year={2018},
  volume={24},
  pages={591-597}
}

• Kallia Apazoglou, S. Farley, +30 authors E. Tzavara
• Published 1 May 2018
• Psychology, Biology
• Nature Medicine

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 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.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.