Extrasynaptic CaMKIIα is involved in the antidepressant effects of ketamine by downregulating GluN2B receptors in an LPS-induced depression model

crossref(2020)

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Abstract
Abstract Background A subanesthetic dose of ketamine provides rapid and effective antidepressant effects, but the molecular mechanism of this treatment remains elusive. Methods In this study, we investigated the role of CaMKIIα in the antidepressant effects of ketamine using an LPS-induced mouse model of depression, explored the different changes of CaMKIIα in the synaptic and extrasynaptic regions of the hippocampus, and clarified the relationship between CaMKIIα and GluN2B from extrasynaptic perspective. Results Ketamine (10 mg/kg, i.p.) administration attenuated the LPS-induced increase in extrasynaptic CaMKIIα activity (p-CaMKIIα) and extrasynaptic GluN2B localization and phosphorylation and that ketamine exerted antidepressant effects. Immunoprecipitation assay revealed that in the extrasynaptic region of the hippocampus, p-CaMKIIα bound to GluN2B, and ketamine administration attenuated the enhanced interaction between p-CaMKIIα and GluN2B induced by LPS. KN93, a CaMKIIα inhibitor, could also reverse the high level of extrasynaptic p-CaMKIIα, reduce hippocampal extrasynaptic GluN2B localization and phosphorylation, and exert antidepressant effects. Additional changes downstream of the ketamine-induced changes in extrasynaptic GluN2B included rescuing the downregulated expression of p-CREB, BDNF, and GluR1 and reversing the impaired induction of LTP in the hippocampus induced by LPS. Conclusion These results indicate that extrasynaptic CaMKIIα plays a key role in the cellular mechanism of ketamine's antidepressant effect and is related to the down-regulation of extrasynaptic GluN2B localization and phosphorylation and further affects synaptic plasticity.
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