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

Abstract

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 IIα (CaMKIIα) is important for GluN2B localization and activity. Here, we tested whether changes of CaMKIIα 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 CaMKIIα 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-CaMKIIα, CaMKIIα, p-GluN2B, GluN2B, p-CREB, CREB, BDNF, GluR1, and GluR2 in the hippocampus were detected by western blotting. The interaction between GluN2B and CaMKIIα 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-CaMKIIα 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-CaMKIIα-GluN2B interaction, which was attenuated by ketamine administration. SiRNA assay revealed that CaMKIIα knockdown reduced the level and number of clusters of GluN2B in the cultured hippocampal neurons. KN93 administration also reduced extrasynaptic p-CaMKIIα expression, extrasynaptic GluN2B localization, and phosphorylation and exerted antidepressant effects.

Ketamine and Calcium Signaling—A Crosstalk for Neuronal Physiology and Pathology

“…In addition, ketamine action delayed induction of GluA1 by 24 h, which was regulated by the activation of CaMKII. Ketamine administration upregulated the expression of p-CREB and BDNF in the hippocampus, preventing the impairment of LTP induction and loss of the synaptic proteins induced by LPS [159]. The above data confirm that Ca 2+ and calmodulin effectively contribute to the control and regulation of synaptic processes.…”

The Calcium/Calmodulin-Dependent Kinases II and IV as Therapeutic Targets in Neurodegenerative and Neuropsychiatric Disorders

“…CaMKII inhibitor prevented the ketamine-induced decrease in immobility in the forced swim test in mice [135]. Similarly, in the mouse model of depression induced by lipopolysaccharide, the extrasynaptic increase in CaMKIIα expression was attenuated by ketamine administration and treatment with CaMKIIα inhibitor KN-93 [136]. These effects were connected with the downregulation of GluN2B receptor localization and phosphorylation in mouse hippocampal neurons.…”

An Integrative Pharmacology-Based Strategy to Uncover the Mechanism of Xiong-Pi-Fang in Treating Coronary Heart Disease with Depression

“…At the same time, cAMP and PKA are also widely distributed in the nervous system, which can guide the regeneration of neurons, improve the plasticity of synapses, and play a role in protecting the nervous system ( Zhang M et al, 2018 ). CREB is involved in a wide range of neural plasticity processes, including neuronal survival, neuroprotection, neurogenesis, synaptic plasticity, and regulation of emotional expression ( Liu et al, 2016 ; Tang et al, 2020 ). BDNF is a classical downstream target gene of CREB, which can nourish nerves and promote the differentiation, increment, and regeneration of neurons ( Wang et al, 2019 ).…”