Background: Proinflammatory cytokines IL-1β has been proposed to be a key mediator in the pathophysiology of mood-related disorders. However, the IL-1 receptor antagonist (IL-1ra) is a natural antagonist of IL-1 and plays a key role in the regulation of IL-1-mediated inflammation, the effects of IL-1ra in stress-induced depression has not been well elucidated.
Methods: Chronic social defeat stress (CSDS) and lipopolysaccharide (LPS) were used to investigate the effects of IL-1ra. ELISA kit and qPCR were used to detect IL-1ra levels. Golgi staining and electrophysiological recordings were used to investigate glutamatergic neurotransmission in the hippocampus. Immunofluorescence and western blotting were used to analyze CREB-BDNF pathway and synaptic proteins.
Results: Serum levels of IL-1ra increased significantly in two animal models of depression, and there was a significant correlation between serum IL-1ra levels and depression-like behaviors. Both CSDS and LPS induced the imbalance of IL-1ra and IL-1β in the hippocampus. Furthermore, chronic intracerebroventricular (i.c.v.) infusion of IL-1ra not only blocked CSDS-induced depression-like behaviors, but also alleviated CSDS-induced decrease in dendritic spine density and impairments in AMPARs-mediated neurotransmission. Finally, IL-1ra treatment produces antidepressant-like effects through the activation of CREB-BDNF in the hippocampus.
Limitation: Further studies need to investigate the effect of IL-1ra in the periphery in CSDS-induced depression.
Conclusion: Our study suggests that the imbalance of IL-1ra and IL-1β reduces the expression of the CREB-BDNF pathway in the hippocampus, which dysregulates AMPARs-mediated neurotransmission, ultimately leading to depression-like behaviors. IL-1ra could be a new potential candidate for the treatment of mood disorders.
Keywords: AMPARs; CREB-BDNF; CSDS; Glutamatergic dysfunction; IL-1ra; Lipopolysaccharide.
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