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

Background A subanesthetic dose of ketamine provides rapid and effective antidepressant effects, but the molecular mechanism remains elusive. It has been reported that overactivation of extrasynaptic GluN2B receptors is associated with the antidepressant effects of ketamine and the interaction between GluN2B and calcium/calmodulin-dependent protein kinase II alpha (CaMKII alpha) is important for GluN2B localization and activity. Here, we tested whether changes of CaMKII alpha and GluN2B are involved in the antidepressant effects of ketamine. Methods Lipopolysaccharide (LPS) was injected intraperitoneally (i.p.) into male C57BL/6 mice. For the interventional study, mice were administrated with ketamine (10 mg/kg, i.p.) or a CaMKII alpha inhibitor KN93. Behavioral alterations were evaluated by open-field, novelty-suppressed feeding, and forced-swimming tests. Physiological functions were evaluated by the body weight and fur coat state of mice. The levels of p-CaMKII alpha, CaMKII alpha, p-GluN2B, GluN2B, p-CREB, CREB, BDNF, GluR1, and GluR2 in the hippocampus were detected by western blotting. The interaction between GluN2B and CaMKII alpha was studied using immunoprecipitation assay and small interfering RNA (siRNA) assays. The colocalizations of GluN2B/PSD95 and p-GluN2B/PSD95 were detected by immunofluorescence. The long-term potentiation (LTP) in SC-CA1 of the hippocampus was detected by electrophysiology. Results LPS injection induced depression-like behaviors, which were accompanied by significant increases in extrasynaptic p-CaMKII alpha expression, extrasynaptic GluN2B localization, and phosphorylation and decreases in p-CREB, BDNF, and GluR1 expressions and LTP impairment. These changes were prevented by ketamine administration. Immunoprecipitation assay revealed that LPS induced an increase in the p-CaMKII alpha-GluN2B interaction, which was attenuated by ketamine administration. SiRNA assay revealed that CaMKII alpha knockdown reduced the level and number of clusters of GluN2B in the cultured hippocampal neurons. KN93 administration also reduced extrasynaptic p-CaMKII alpha expression, extrasynaptic GluN2B localization, and phosphorylation and exerted antidepressant effects. Conclusion These results indicate that extrasynaptic CaMKII alpha plays a key role in the cellular mechanism of ketamine's antidepressant effect and it is related to the downregulation of extrasynaptic GluN2B localization and phosphorylation.