Antidepressive effects of targeting ELK-1 signal transduction

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.Medicin

Antidepressive effects of targeting ELK-1 signal transduction

International audienceDepression, 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

Antidepressive effects of targeting ELK-1 signal transduction

International audienceDepression, a devastating psychiatric disorder, is a leadingcause of disability worldwide. Current antidepressants addressspecific symptoms of the disease, but there is vast roomfor improvement1. In this respect, new compounds that actbeyond classical antidepressants to target signal transductionpathways governing synaptic plasticity and cellular resilienceare highly warranted2–4. The extracellular signal–regulatedkinase (ERK) pathway is implicated in mood regulation5–7, butits pleiotropic functions and lack of target specificity prohibitoptimal drug development. Here, we identified the transcriptionfactor ELK-1, an ERK downstream partner8, as a specificsignaling module in the pathophysiology and treatment ofdepression that can be targeted independently of ERK. ELK1mRNA was upregulated in postmortem hippocampal tissuesfrom depressed suicides; in blood samples from depressedindividuals, failure to reduce ELK1 expression was associatedwith resistance to treatment. In mice, hippocampal ELK-1 overexpressionper se produced depressive behaviors; conversely,the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states inducedby stress. Our work stresses the importance of target selectivityfor a successful approach for signal-transduction-basedantidepressants, singles out ELK-1 as a depression-relevanttransducer downstream of ERK and brings proof-of-conceptevidence for the druggability of ELK-1