Antidepressive effects of targeting ELK-1 signal transduction

• Published in: Nature Medicine Vol. 24; no. 5; pp. 591 - 597
• Main Authors: Apazoglou, Kallia, Farley, Séverine, Gorgievski, Victor, Belzeaux, Raoul, Lopez, Juan Pablo, Grenier, Julien, Ibrahim, El Chérif, El Khoury, Marie-Anne, Tse, Yiu C., Mongredien, Raphaele, Barbé, Alexandre, de Macedo, Carlos E. A., 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 P., Caboche, Jocelyne, Turecki, Gustavo, Giros, Bruno, Tzavara, Eleni T.
• Format: Journal Article Magazine Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2018; Nature Publishing Group
• Subjects: 631/378/1689/1414; 692/53/2422; 692/699/476/1414; Adult; Animals; Antidepressants; Antidepressive Agents - pharmacology; Behavior, Animal; Behavioral plasticity; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cellular signal transduction; Depression (Mood disorder); Depression - blood; Depression - genetics; Depression - physiopathology; Development and progression; Drug development; Drug therapy; ets-Domain Protein Elk-1 - blood; ets-Domain Protein Elk-1 - genetics; ets-Domain Protein Elk-1 - metabolism; Extracellular signal-regulated kinase; Extracellular signal-regulated kinases; Female; Health aspects; Hippocampus; Hippocampus - metabolism; Humans; Infectious Diseases; Job stress; Letter; Life Sciences; Major depressive disorder; Male; Mental depression; Mental disorders; Messenger RNA; Metabolic Diseases; Metabolic pathways; Mice; Middle Aged; Molecular chains; Molecular Medicine; Mood; Neuronal Plasticity; Neurons and Cognition; Neurosciences; Pharmacological research; Physiological aspects; Plastic foam; Plasticity; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal transduction; Signal Transduction - drug effects; Stress, Psychological - complications; Suicide; Synaptic plasticity; Transcription factors; Tricyclic antidepressants
• ISSN: 1078-8956; 1546-170X; 1744-7933
• DOI: 10.1038/s41591-018-0011-0

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 improvement
1
. In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted
2
–
4
. The extracellular signal–regulated kinase (ERK) pathway is implicated in mood regulation
5
–
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 partner
8
, 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.