Hippocampal CA1 βCaMKII mediates neuroinflammatory responses via COX-2/PGE2 signaling pathways in depression

Abstract

BackgroundNeuroinflammation has recently emerged as a critical risk factor in the pathophysiology of depression. However, the underlying molecular mechanisms and the development of novel therapeutic strategies as means to target these inflammatory pathways for use in the treatment of depression remain unresolved. In the present study, we aimed to investigate the molecular events of neuroinflammation as related to its induction of depression-like behaviors.MethodsChronic unpredictable mild stress (CUMS) or lipopolysaccharide (LPS) was used to induce depression-like behaviors in rats. The inflammatory factors and related proteins were verified by RT-PCR, immunoblotting, and immunofluorescence assay. In vivo intracerebral injection of adenovirus-associated virus (AAV) in rats was used to overexpress or block the function of the β form of the calcium/calmodulin-dependent protein kinase type II (βCaMKII). In vivo intracerebroventricular injection of SB203580 was used to block p38 mitogen-activated protein kinase (MAPK). Finally, the prostaglandin E2 (PGE2) concentration was verified by using enzyme-linked assay kit.ResultsThe expression of cyclo-oxygenase (COX)-2, which is responsible for production of the pro-inflammatory factor PGE2 and thus glial activation, was increased in the CA1 hippocampus in a rat model of depression. Further, the βCaMKII in CA1 was significantly upregulated in depressed rats, while antidepressant treatment downregulated this kinase. Overexpression of βCaMKII via infusion of a constructed AAV-βCaMKII into the CA1 region resulted in phosphorylation of the p38 MAPK and the activating transcription factor 2 (ATF2). These effects were accompanied by an enhanced activity of the COX-2/PGE2 pathway and effectively induced core symptoms of depression. Conversely, knockdown of βCaMKII within the CA1 region reversed these inflammation-related biochemical parameters and significantly rescued depression symptoms.ConclusionThese results demonstrate that βCaMKII can act as a critical regulator in depression via activating neuroinflammatory pathways within the CA1 region. Moreover, this study provides new perspectives on molecular targets and drug therapies for future investigation in the treatment of depression.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1377-0) contains supplementary material, which is available to authorized users.

<p>Electroacupuncture Relieves LPS-Induced Depression-Like Behaviour in Rats Through IDO-Mediated Tryptophan-Degrading Pathway</p>

“…43 As an immune activator and cytokine inducer, LPS can lead to immune activation and inflammatory cytokine release, thereby causing depression-like behaviour in rats. 33,44 A previous study found that acupuncture could effectively suppress neuroinflammation in the hippocampus of a stress-induced depression rat model. 45 Therefore, the contents of IL-1β, IL-6, and TNFα in the plasma and hippocampus were measured in this study.…”

“…LPS was dissolved in sterile 0.9% saline at a concentration of 0.1 mg/mL and intraperitoneally injected into the Wistar rats at a dosage of 0.5 mg/kg daily for 1 week to induce depression-like behaviours. The dose was based on previously reported studies 32,33 and verified in our preliminary studies.…”

“…The SPT was conducted as described previously with minor modifications. 33 For the first 24 hours, all rats were given two bottles containing 1% sucrose solution; for the second 24 hours, they were given a bottle of water and a bottle containing 1% sucrose solution. At the 12th hour, the positions of the bottle containing the sucrose solution and the water bottle were changed.…”

CaMKIIβ in Neuronal Development and Plasticity: An Emerging Candidate in Brain Diseases

“…A similar manipulation of CaMKIIβ (overexpression and downregulation) in the CA1 gives similar results on depressive-like behavior [ 69 ]. CaMKIIβ seems to act upstream of the cyclo-oxygenase (COX)-2/prostaglandin E2 (PGE2) neuroinflammatory signaling pathway in this hippocampal region [ 69 ].…”

“…Indeed, its expression is increased at the mRNA level in the human frontal cortex of depression tissues [ 65 ] and, at the protein level, CaMKIIβ is significantly upregulated in the lateral habenula (nucleus that has emerged as a key brain region in aversive behaviors and the pathophysiology of depression) of animal models of depression and down-regulated by antidepressants [ 68 ]. Similarly, in the hippocampal CA1, CaMKIIβ is significantly upregulated in depressed rats, while antidepressant treatment downregulated this protein [ 69 ]. Furthermore, increasing CaMKIIβ in the lateral habenula through a viral approach is sufficient for producing profound depressive symptoms, including anhedonia and behavioral despair, in both rats and mice [ 68 ].…”