Abstract
Stress can be a motivational force for decisive action and adapting to novel environment; whereas, exposure to chronic stress contributes to the development of depression and anxiety. However, the molecular mechanisms underlying stress-responsive behaviors are not fully understood. Here, we identified the orphan receptor GPR158 as a novel regulator operating in the prefrontal cortex (PFC) that links chronic stress to depression. GPR158 is highly upregulated in the PFC of human subjects with major depressive disorder. Exposure of mice to chronic stress also increased GPR158 protein levels in the PFC in a glucocorticoid-dependent manner. Viral overexpression of GPR158 in the PFC induced depressive-like behaviors. In contrast GPR158 ablation, led to a prominent antidepressant-like phenotype and stress resiliency. We found that GPR158 exerts its effects via modulating synaptic strength altering AMPA receptor activity. Taken together, our findings identify a new player in mood regulation and introduce a pharmacological target for managing depression.
Highlights
An individual’s emotional response to stress is determined by genetic and environmental factors
Addressing the mechanisms involved we found no change in Bdnf mRNA levels but we observed a decrease in the phosphorylation level of the eukaryotic elongation factor 2, suggesting that the increase brain derived neurotrophic factor (BDNF) levels in Gpr158À/À medial prefrontal cortex (mPFC) may be due to local synthesis (Figure 8D–E)
Several lines of evidence obtained in this study suggest that orphan receptor GPR158 may be one of the key molecular factors determining an individual’s susceptibility or resiliency to stress-induced depression
Summary
An individual’s emotional response to stress is determined by genetic and environmental factors. Exposure to stressful events is thought to underlie long-term neuroadaptations observed in MDD including dendritic remodeling, spine loss, and altered synaptic transmission (Arnsten, 2015; Radley et al, 2006). Much of these effects are mediated by the glucocorticoids whose unrestraint release during chronic stress often triggers development of maladaptive responses (Myers et al, 2014). The roles of stress-induced genes in mediating cellular changes in mPFC and driving maladaptive behavioral phenotypes are not well understood. We show involvement of GPR158 in pathology of MDD in humans and demonstrate that manipulation with GPR158 in animal models produces antidepressive-like behaviors and stress resilience
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