Ryanodine receptors are involved in the improvement of depression-like behaviors through electroconvulsive shock in stressed mice

Background: Electroconvulsive therapy (ECT) is effective for treating depression. However, the mechanisms underlying the antidepressant effects of ECT remain unknown. Depressed patients exhibit abnormal Ca2+ kinetics. Early stages of the intracellular Ca2+ signaling pathway involve the release of Ca2+ from the endoplasmic reticulum (ER) via Ca2+ release channels. Objective: We considered that depression may be improved via ECT-induced normalization of intracellular Ca2+ regulation through the Ca2+ release channels. The current study aimed to investigate the effects of ECT on two Ca2+ release channels, ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs). Methods: A mouse depression-like model subjected to water immersion with restraint stress was administered electroconvulsive shock (ECS) therapy. Their depression-like status was behaviorally and histologically assessed using forced swimming tests, novelty-suppressed feeding tests, and by evaluating neurogenesis in the hippocampal dentate gyrus, respectively. A RyRs blocker, dantrolene, was administered prior to ECS, and the changes in depression-like conditions were examined. Results: The protein expressions of RyR1 and RyR3 significantly increased in the hippocampus of the mouse model with depression-like symptoms. This increase was attenuated as depression-like symptoms were reduced due to ECS application. However, pre-injection with dantrolene reduced the antidepressant effects of ECS. Conclusions: A significant increase in RyRs expression in a depression-like state and exacerbation of depression-like symptoms by RyRs inhibitors may be caused by RyRs dysfunction, suggesting over expression of RyRs is a compensatory effect. Normalization of RyRs expression levels by ECS suggests that ECT normalizes the Ca2+ release via RyRs. Thus, normalizing the function of RyRs may play an important role in the therapeutic effect of ECT. (c) 2020 The Authors. Published by Elsevier Inc.

Automated summary

This study found that the protein expressions of RyR1 and RyR3 significantly increased in the hippocampus of mouse models with depression-like symptoms, and ECS therapy could attenuate this increase and improve depression symptoms. However, pre-injection with RyRs blocker dantrolene reduced the antidepressant effects of ECS.