Antidepressive effects of targeting ELK-1 signal transduction

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

GPR56/ADGRG1 is associated with response to antidepressant treatment

“…Our results above suggest that GPR56 may be involved in mechanisms associated with antidepressant response that are common to different classes of antidepressants, but interestingly, not involved in mechanisms of placebo response. To further examine the potential function and regulation of Gpr56 in depression and antidepressant response, we conducted studies in animals, using the unpredictable chronic mild stress (UCMS) paradigm, a well validated murine model of depression 5 , followed by treatment with fluoxetine, a standard SSRI, to model antidepressant effects ( Fig. 2a).…”

“…In this model, stress-exposure leads to depressive-like behaviors (displayed as increased anhedonia and/ or resignation) that can be alleviated by subsequent administration of an antidepressant. We have previously adapted this model to distinguish between responder and non-responder mice 5 . Here, chronic stress-induced depressive-like behaviors were effectively reversed in 60% (responders) of the fluoxetine-treated mice.…”

“…Pharmacological effects and response to antidepressants in UCMS-subjected mice were assessed with a reversal protocol (45 days of UCMS; treatment during the last 3 weeks) as previously described 5 . Namely, mice were subjected to the UCMS-protocol for 45 days starting Day 0.…”

Commentary: Antidepressive effects of targeting ELK-1 signal transduction

“…Recently, Dr. Tzavara's group at Sorbonne University in France reported that ELK-1, a transcription factor (TF) and a major downstream target of the ERK signaling pathway, is upregulated both in depressive suicides and in animal models of depression induced by unpredictable chronic mild stress (UCMS) and social defeat (Apazoglou et al, 2018 ). They also found that patients who responded to antidepressant treatment had significantly lower blood levels of ELK-1 than nonresponders.…”

“…Furthermore, the authors showed that virally overexpressing ELK-1 in the dentate gyrus (DG) of mice induced depression-like behaviors. Injection of blood–brain barrier-permeable TAT-DEF-ELK-1 (TDE) peptide, which disrupts ERK-mediated ELK-1 phosphorylation (activation) in the DG, improved behavioral signs in the depression models and in mice overexpressing ELK-1, without affecting basal levels of locomotion and memory (Lavaur et al, 2007 ; Apazoglou et al, 2018 ). The authors conclude that the induced expression of genes by enhanced ELK-1 activity may be critical for depressive symptoms.…”