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Nat Med. 2018 May;24(5):591-597. doi: 10.1038/s41591-018-0011-0. Epub 2018 May 7.

Antidepressive effects of targeting ELK-1 signal transduction.

Author information

1
Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France.
2
Department of Psychiatry, Douglas Mental Health University Institute, McGill University Faculty of Medicine, Montreal, Quebec, Canada.
3
Assistance Publique Hôpitaux de Marseille, Sainte Marguerite Hospital, Pôle de Psychiatrie Universitaire Solaris, Marseille, France.
4
FondaMental Foundation, Créteil, France.
5
INSERM UMR-S 1124 ERL 3649, Université Paris Descartes, Paris, France.
6
Aix Marseille Université, CNRS, INT, Institut des Neurosciences de la Timone, UMR 7289, Marseille, France.
7
Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, Université de Bordeaux, Bordeaux, France.
8
Department of Neuropsychiatry, Department of Psychiatry and Psychotherapy and NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Berlin, Germany.
9
Oramacell, Paris, France.
10
Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France. bruno.giros@mcgill.ca.
11
Department of Psychiatry, Douglas Mental Health University Institute, McGill University Faculty of Medicine, Montreal, Quebec, Canada. bruno.giros@mcgill.ca.
12
FondaMental Foundation, Créteil, France. bruno.giros@mcgill.ca.
13
Neuroscience Paris Seine-IBPS, INSERM UMRS 1130/CNRS UMR8246, Sorbonne University, Université Pierre et Marie Curie, Paris, France. eleni.tzavara@inserm.fr.
14
FondaMental Foundation, Créteil, France. eleni.tzavara@inserm.fr.

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 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 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 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.

PMID:
29736027
DOI:
10.1038/s41591-018-0011-0

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