Abstract
Extracellular signal-regulated kinase 1/2- (ERK1/2-) mediated cellular signaling plays a major role in synaptic and structural plasticity. Although ERK1/2 signaling has been shown to be involved in stress and depression, whether vulnerability to develop depression is associated with abnormalities in ERK1/2 signaling is not clearly known. The present study examined ERK1/2 signaling in frontal cortex and hippocampus of rats that showed vulnerability (learned helplessness, (LH)) or resiliency (non-learned helplessness, (non-LH)) to developing stress-induced depression. In frontal cortex and hippocampus of LH rats, we found that mRNA and protein expressions of ERK1 and ERK2 were significantly reduced, which was associated with their reduced activation and phosphorylation in cytosolic and nuclear fractions, where ERK1 and ERK2 target their substrates. In addition, ERK1/2-mediated catalytic activities and phosphorylation of downstream substrates RSK1 (cytosolic and nuclear) and MSK1 (nuclear) were also lower in the frontal cortex and hippocampus of LH rats without any change in their mRNA or protein expression. None of these changes were evident in non-LH rats. Our study indicates that ERK1/2 signaling is differentially regulated in LH and non-LH rats and suggests that abnormalities in ERK1/2 signaling may be crucial in the vulnerability to developing depression.
Highlights
Depression is a debilitating psychiatric illness with a lifetime prevalence rate of about 5–20% [1,2,3]
There were no significant differences between NLH and tested control (TC) groups (Figure 1)
We found that there is hypoactivation of Extracellular signal-regulated kinases 1/2 (ERK1/2) signaling in the brain of learned helplessness (LH) rats
Summary
Depression is a debilitating psychiatric illness with a lifetime prevalence rate of about 5–20% [1,2,3]. Extracellular signal-regulated kinases 1/2 (ERK1/2) signaling, which belongs to a large family of mitogen-activated protein kinase signaling cascades, has consistently been shown to have a major impact on both synaptic plasticity and structural plasticity. This is evident from studies showing their role in long-term potentiation, long-term depression, and the regulation of neuronal survival via neurotrophic/growth factors [10,11,12]. The non-learned helpless animals (non-LH, resilient), given the same uncontrollable and unpredictable stress, fail to show such responses This provides an opportunity to distinguish the neurobiological factors associated with resiliency versus vulnerability to developing depression. We examined functional significance of altered ERK1 and ERK2 by determining activation and expression of their downstream common substrates RSK (90 kDa S6 kinase) and MSK (mitogen and stress-activated kinase)
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