Enhancement of AMPA receptor (AMPAR) function has emerged as a novel strategy for treatment of depression. Nevertheless, studies on AMPAR function in chronic animal models used to predict antidepressant efficacy are surprisingly lacking. We investigated the role of AMPARs in antidepressant action in an unpredictable chronic mild stress (UCMS) model in BALB/c mice. After 3 wk of UCMS, BALB/c mice developed a number of depressive-like behaviours that were successfully prevented by fluoxetine (20 mg/kg) administration. The AMPAR potentiator LY392098 [N-2-(4-(3-thienyl)phenyl)propyl 2-propanesulfonamide] (5 mg/kg), when administered alone, functioned like classic antidepressants by reducing weight loss, fur deterioration and immobility in the tail suspension test. However, LY392098 did not restore sucrose preference and did not reduce anxiety (marble-burying) in stressed mice. In the same protocol, the AMPAR antagonist GYKI (10 mg/kg) reversed most, but not all, of the antidepressant-like actions of fluoxetine. Thus, the antidepressant-like effects of LY392098 were fully predicted by the AMPAR dependence of effects demonstrated for fluoxetine. Our results demonstrate that, in the UCMS paradigm, AMPAR activation exhibits antidepressant-like activity that relates preferentially to specific depressive-like responses and that those specific responses can be defined by their regulation by AMPAR modulation under conditions of stress.

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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.