Editors' ChoiceDepression

ELK-1: A molecular substrate of depression

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Science Translational Medicine  13 Jun 2018:
Vol. 10, Issue 445, eaau0468
DOI: 10.1126/scitranslmed.aau0468

Abstract

Converging data from depressed patients and rodent chronic stress models implicate ELK-1, a stress-related transcription factor, in the pathophysiology of depression.

Motivated by the serendipitous discovery of the antidepressant effects of monoamine oxidase inhibitors, almost all existing antidepressant medications target serotonin and other monoamine neuromodulators. These drugs typically require weeks to achieve full remission and are ineffective in up to one-third of patients. Thus, there is a pressing clinical need for new compounds targeting other depression-related signaling pathways.

The extracellular signal–regulated kinase (ERK) has been implicated in depression, but it regulates many downstream signaling molecules with heterogeneous and antagonistic functions, complicating drug discovery efforts. Apazoglou et al. present converging data from patients and mouse models that implicate ELK-1, a downstream transcription factor regulated by the ERK pathway, in the pathophysiology of depression. ELK-1 expression was selectively increased in postmortem hippocampal brain tissue in depressed patients and in multiple rodent models of chronic stress and depression behavior. Overexpressing ELK-1 in the hippocampus was sufficient to drive depression-related behavior in normal mice. Conversely, inhibiting ELK-1 activation—by treating mice with a drug that interferes with its interaction with ERK—reversed the effects of stress on hippocampal LTP, neurotrophin signaling, and depressive behavior. ELK-1 activation was also correlated with treatment response in patients; citalopram, a commonly prescribed antidepressant, reduced peripheral blood levels of ELK-1 in patients whose depressive symptoms resolved after treatment but not in nonresponders. Importantly, this result was replicated in an independent cohort of depressed patients.

Depression is approximately twice as common in women as in men, and further studies are needed to evaluate the role of ELK-1 signaling in women. All mice and most patients in this work were male, and recent studies indicate that depression is associated with sexually dimorphic transcriptional signatures, including sex-specific effects on ERK-related gene expression profiles. Depression is also a highly heterogeneous syndrome, both clinically and biologically. Depression has been associated with decreased ERK pathway signaling in prior work, suggesting that different mediators downstream of ERK may have opposing effects on mood or that distinct mechanisms may be involved in different forms of depression. Thus, it will be important to determine whether increased ELK-1 signaling is important in just a subset of patients who might preferentially benefit from ELK-1–targeting drugs.

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