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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Perlis, R. H. Abandoning personalization to get to precision in the pharmacotherapy of depression. World Psychiatry 15, 228–235 (2016).
Ionescu, D. F. & Papakostas, G. I. Experimental medication treatment approaches for depression. Transl. Psychiatry 7, e1068 (2017).
Yuan, L. L., Wauson, E. & Duric, V. Kinase-mediated signaling cascades in mood disorders and antidepressant treatment. J. Neurogenet. 30, 178–184 (2016).
Jeon, S. W. & Kim, Y. K. Molecular neurobiology and promising new treatment in depression. Int. J. Mol. Sci. 17, 381 (2016).
Duman, C. H., Schlesinger, L., Kodama, M., Russell, D. S. & Duman, R. S. A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment. Biol. Psychiatry 61, 661–670 (2007).
Einat, H. et al. The role of the extracellular signal–regulated kinase signaling pathway in mood modulation. J. Neurosci. 23, 7311–7316 (2003).
Labonté, B. et al. Sex-specific transcriptional signatures in human depression. Nat. Med. 23, 1102–1111 (2017).
Janknecht, R., Ernst, W. H., Pingoud, V. & Nordheim, A. Activation of ternary complex factor Elk-1 by MAP kinases. EMBO J. 12, 5097–5104 (1993).
Gould, T. D. & Manji, H. K. Signaling networks in the pathophysiology and treatment of mood disorders. J. Psychosom. Res. 53, 687–697 (2002).
Duric, V. et al. A negative regulator of MAP kinase causes depressive behavior. Nat. Med. 16, 1328–1332 (2010).
Popoli, M., Yan, Z., McEwen, B. S. & Sanacora, G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 13, 22–37 (2011).
Tse, Y. C., Bagot, R. C., Hutter, J. A., Wong, A. S. & Wong, T. P. Modulation of synaptic plasticity by stress hormone associates with plastic alteration of synaptic NMDA receptor in the adult hippocampus. PLoS One 6, e27215 (2011).
Revest, J. M. et al. The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids. Nat. Neurosci. 8, 664–672 (2005).
Gutièrrez-Mecinas, M. et al. Long-lasting behavioral responses to stress involve a direct interaction of glucocorticoid receptors with ERK1/2-MSK1-Elk-1 signaling. Proc. Natl. Acad. Sci. USA 108, 13806–13811 (2011).
Belzeaux, R. et al. Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode. Transl. Psychiatry 2, e185 (2012).
Menke, A. et al. Dexamethasone stimulated gene expression in peripheral blood is a sensitive marker for glucocorticoid receptor resistance in depressed patients. Neuropsychopharmacology 37, 1455–1464 (2012).
Vythilingam, M. et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am. J. Psychiatry 159, 2072–2080 (2002).
Turecki, G., Ernst, C., Jollant, F., Labonté, B. & Mechawar, N. The neurodevelopmental origins of suicidal behavior. Trends Neurosci. 35, 14–23 (2012).
Farley, S., Apazoglou, K., Witkin, J. M., Giros, B. & Tzavara, E. T. Antidepressant-like effects of an AMPA receptor potentiator under a chronic mild stress paradigm. Int. J. Neuropsychopharmacol. 13, 1207–1218 (2010).
Tsankova, N. M. et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat. Neurosci. 9, 519–525 (2006).
Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).
Lopez, J. P. et al. miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment. Nat. Med. 20, 764–768 (2014).
Nilsson, M. et al. Elk1 and SRF transcription factors convey basal transcription and mediate glucose response via their binding sites in the human LXRB gene promoter. Nucleic Acids Res. 35, 4858–4868 (2007).
Chen, E., Miller, G. E., Kobor, M. S. & Cole, S. W. Maternal warmth buffers the effects of low early-life socioeconomic status on pro-inflammatory signaling in adulthood. Mol. Psychiatry 16, 729–737 (2011).
Yang, C. H., Huang, C. C. & Hsu, K. S. A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes. J. Neurosci. 32, 7550–7562 (2012).
Lavaur, J. et al. A TAT-DEF-Elk-1 peptide regulates the cytonuclear trafficking of Elk-1 and controls cytoskeleton dynamics. J. Neurosci. 27, 14448–14458 (2007).
Jacobs, D., Glossip, D., Xing, H., Muslin, A. J. & Kornfeld, K. Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev. 13, 163–175 (1999).
Sharrocks, A. D., Yang, S. H. & Galanis, A. Docking domains and substrate-specificity determination for MAP kinases. Trends Biochem. Sci. 25, 448–453 (2000).
Besnard, A. et al. Alterations of molecular and behavioral responses to cocaine by selective inhibition of Elk-1 phosphorylation. J. Neurosci. 31, 14296–14307 (2011).
Crozatier, C. et al. Calcineurin (protein phosphatase 2B) is involved in the mechanisms of action of antidepressants. Neuroscience 144, 1470–1476 (2007).
Svenningsson, P. et al. Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac). Proc. Natl. Acad. Sci. USA 99, 3182–3187 (2002).
Mouri, A. et al. Involvement of a dysfunctional dopamine-D1/N-methyl-d-aspartate-NR1 and Ca2+/calmodulin-dependent protein kinase II pathway in the impairment of latent learning in a model of schizophrenia induced by phencyclidine. Mol. Pharmacol. 71, 1598–1609 (2007).
Manji, H. K. et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol. Psychiatry 53, 707–742 (2003).
Duman, R. S., Aghajanian, G. K., Sanacora, G. & Krystal, J. H. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat. Med. 22, 238–249 (2016).
Nasca, C. et al. Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity. Proc. Natl. Acad. Sci. USA 112, 14960–14965 (2015).
Guilloux, J. P., Seney, M., Edgar, N. & Sibille, E. Integrated behavioral z-scoring increases the sensitivity and reliability of behavioral phenotyping in mice: relevance to emotionality and sex. J. Neurosci. Methods 197, 21–31 (2011).
Dwivedi, Y. et al. Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects. J. Neurochem. 77, 916–928 (2001).
Qi, X. et al. Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress. Neurobiol. Dis. 31, 278–285 (2008).
Svenningsson, P. et al. Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation. J. Neurosci. 27, 4201–4209 (2007).
Brami-Cherrier, K. et al. Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice. J. Neurosci. 25, 11444–11454 (2005).
Nolte, J. The Human Brain: An Introduction to its Functional Anatomy (Mosby/Elsevier, Philadelphia, 2009).
Uher, R. et al. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am. J. Psychiatry 171, 1278–1286 (2014).
Bell, J. A., Kivimäki, M., Bullmore, E. T., Steptoe, A. & Carvalho, L. A. Repeated exposure to systemic inflammation and risk of new depressive symptoms among older adults. Transl. Psychiatry 7, e1208 (2017).
Consoloni, J. L. et al. Serotonin transporter gene expression predicts the worsening of suicidal ideation and suicide attempts along a long-term follow-up of a major depressive episode. Eur. Neuropsychopharmacol. 28, 401–414 (2018).
Hervé, M. et al. Translational identification of transcriptional signatures of major depression and antidepressant response. Front. Mol. Neurosci. 10, 248 (2017).
Tzavara, E. T. et al. M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies. FASEB J. 18, 1410–1412 (2004).
Paxinos, G. & Franklin, K. B. J. The Mouse Brain In Stereotaxic Coordinates (Gulf Professional Publishing, Houston, 2003).
Li, X., Need, A. B., Baez, M. & Witkin, J. M. Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice. J. Pharmacol. Exp. Ther. 319, 254–259 (2006).
Mombereau, C. et al. Genetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety- and antidepressant-like behavior. Neuropsychopharmacology 29, 1050–1062 (2004).
Dulawa, S. C. & Hen, R. Recent advances in animal models of chronic antidepressant effects: the novelty-induced hypophagia test. Neurosci. Biobehav. Rev. 29, 771–783 (2005).
Gur, T. L. et al. cAMP response element-binding protein deficiency allows for increased neurogenesis and a rapid onset of antidepressant response. J. Neurosci. 27, 7860–7868 (2007).
Kruk-Slomka, M., Michalak, A., Budzynska, B. & Biala, G. A comparison of mecamylamine and bupropion effects on memory-related responses induced by nicotine and scopolamine in the novel object recognition test in mice. Pharmacol. Rep. 66, 638–646 (2014).
Tzavara, E. T. et al. Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications. Biol. Psychiatry 59, 508–515 (2006).
Hancock, C. N. et al. Identification of novel extracellular signal-regulated kinase docking domain inhibitors. J. Med. Chem. 48, 4586–4595 (2005).
Dournes, C., Beeské, S., Belzung, C. & Griebel, G. Deep brain stimulation in treatment-resistant depression in mice: comparison with the CRF1 antagonist, SSR125543. Prog. Neuropsychopharmacol. Biol. Psychiatry 40, 213–220 (2013).
Moutsimilli, L. et al. Antipsychotics increase vesicular glutamate transporter 2 (VGLUT2) expression in thalamolimbic pathways. Neuropharmacology 54, 497–508 (2008).
Meffre, D. et al. Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum. Proc. Natl. Acad. Sci. USA 112, 7587–7592 (2015).
Viereckel, T. et al. Midbrain gene screening identifies a new mesoaccumbal glutamatergic pathway and a marker for dopamine cells neuroprotected in Parkinson's disease. Sci. Rep. 6, 35203 (2016).
Morice, E. et al. Defective synaptic transmission and structure in the dentate gyrus and selective fear memory impairment in the Rsk2 mutant mouse model of Coffin-Lowry syndrome. Neurobiol. Dis. 58, 156–168 (2013).
Errington, M. L., Bliss, T. V., Morris, R. J., Laroche, S. & Davis, S. Long-term potentiation in awake mutant mice. Nature 387, 666–667 (1997).
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.
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.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
The super-cooling compound icilin stimulates c-Fos and Egr-1 expression and activity involving TRPM8 channel activation, Ca2+ ion influx and activation of the ternary complex factor Elk-1
Biochemical Pharmacology (2020)
Nature Communications (2020)
Stimulation of TRPM3 channels increases the transcriptional activation potential of Elk-1 involving cytosolic Ca2+, extracellular signal-regulated protein kinase, and calcineurin
European Journal of Pharmacology (2019)
The high efficacy of muscarinic M4 receptor in D1 medium spiny neurons reverses striatal hyperdopaminergia
BI ou pas trop BI : quels marqueurs pour différencier les troubles bipolaires des troubles dépressifs majeurs ?
French Journal of Psychiatry (2019)