TNF-α from hippocampal microglia induces working memory deficits by acute stress in mice

Ohgidani, Masahiro; Kato, Takahiro A.; Sagata, Noriyuki; Hayakawa, Kohei; Shimokawa, Norihiro; Sato-Kasai, Mina; Kanba, Shigenobu

doi:10.1016/j.bbi.2015.08.022

Cited by 62 publications

(45 citation statements)

References 34 publications

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“…Primary microglial cells were prepared from the whole brain of 8-week-old male C57BL/6 J mice (CLEA Japan, Inc., Tokyo, Japan) using a magnetic-activated cell sorting as we have reported [ 13 ]. Mouse brain tissues were dissociated enzymatically with a neural tissue dissociation kit (Miltenyi Biotec, Auburn, CA) according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, acute stress is shown to increase the amount of TNFα produced by ramified microglia in the hippocampus of rodent brain. In addition, administration of etanercept, a TNFα inhibitor, can prevent the deficits of spatial working memory induced by acute stress in accordance with a decrease in the expression of TNFα in rodent hippocampus [ 13 ]. Thus, TNF-α inhibitors might slow down cognitive decline and improve daily activities of patients suffered from AD through the modulation of microglial functions [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Donepezil suppresses intracellular Ca2+ mobilization through the PI3K pathway in rodent microglia

Haraguchi

Mizoguchi

Ohgidani

et al. 2017

J Neuroinflammation

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BackgroundMicroglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer’s disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca2+ signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca2+ signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca2+ mobilization in microglial cells.MethodsWe examined whether pretreatment with donepezil affects the intracellular Ca2+ mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells.ResultsIn this study, we observed that pretreatment with donepezil suppressed the TNFα-induced sustained intracellular Ca2+ elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNFα-induced intracellular Ca2+ elevation through the nicotinic α7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFα-mediated intracellular Ca2+ elevation. Pretreatment with donepezil suppressed the TNFα-induced intracellular Ca2+ elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNFα treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway.ConclusionsThese suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1033-0) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Donepezil suppresses intracellular Ca2+ mobilization through the PI3K pathway in rodent microglia

Haraguchi

Mizoguchi

Ohgidani

et al. 2017

J Neuroinflammation

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“…Inflammation and the central release of inflammatory cytokines have been proposed as a mechanism underlying cognitive decline or dysfunction in mouse models of AD [reviewed in Mosher and Wyss-Coray ( 147 )], stress ( 148 ), cancer-treatment (e.g., irradiation and chemotherapy) ( 149 , 150 ), multiple sclerosis ( 151 ), and obesity ( 152 ). The degeneration of the basal forebrain cholinergic system is a factor in many forms of dementia: not only in AD, but also in Parkinson’s disease, Down syndrome, ALS, and supranuclear palsy [see Ferreira-Vieira et al ( 60 )].…”

Section: Clinical Applicationsmentioning

confidence: 99%

The Cholinergic System Modulates Memory and Hippocampal Plasticity via Its Interactions with Non-Neuronal Cells

2017

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Degeneration of central cholinergic neurons impairs memory, and enhancement of cholinergic synapses improves cognitive processes. Cholinergic signaling is also anti-inflammatory, and neuroinflammation is increasingly linked to adverse memory, especially in Alzheimer’s disease. Much of the evidence surrounding cholinergic impacts on the neuroimmune system focuses on the α7 nicotinic acetylcholine (ACh) receptor, as stimulation of this receptor prevents many of the effects of immune activation. Microglia and astrocytes both express this receptor, so it is possible that some cholinergic effects may be via these non-neuronal cells. Though the presence of microglia is required for memory, overactivated microglia due to an immune challenge overproduce inflammatory cytokines, which is adverse for memory. Blocking these exaggerated effects, specifically by decreasing the release of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6), has been shown to prevent inflammation-induced memory impairment. While there is considerable evidence that cholinergic signaling improves memory, fewer studies have linked the “cholinergic anti-inflammatory pathway” to memory processes. This review will summarize the current understanding of the cholinergic anti-inflammatory pathway as it relates to memory and will argue that one mechanism by which the cholinergic system modulates hippocampal memory processes is its influence on neuroimmune function via the α7 nicotinic ACh receptor.

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“…Recent immunological studies have suggested that immune cell activities, including microglia, are modulated by the circadian clock system (33), methylation (34), and/or external stress (35), which may contribute to the activation patterns of microglia during clinical courses of bipolar disorder.…”

Section: Limitation and Future Perspectivesmentioning

confidence: 99%

Microglial CD206 Gene Has Potential as a State Marker of Bipolar Disorder

et al. 2017

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The pathophysiology of bipolar disorder, especially the underlying mechanisms of the bipolarity between manic and depressive states, has yet to be clarified. Microglia, immune cells in the brain, play important roles in the process of brain inflammation, and recent positron emission tomography studies have indicated microglial overactivation in the brain of patients with bipolar disorder. We have recently developed a technique to induced microglia-like (iMG) cells from peripheral blood (monocytes). We introduce a novel translational approach focusing on bipolar disorder using this iMG technique. We hypothesize that immunological conditional changes in microglia may contribute to the shift between manic and depressive states, and thus we herein analyzed gene profiling patterns of iMG cells from three patients with rapid cycling bipolar disorder during both manic and depressive states, respectively. We revealed that the gene profiling patterns are different between manic and depressive states. The profiling pattern of case 1 showed that M1 microglia is dominant in the manic state compared to the depressive state. However, the patterns of cases 2 and 3 were not consistent with the pattern of case 1. CD206, a mannose receptor known as a typical M2 marker, was significantly downregulated in the manic state among all three patients. This is the first report to indicate the importance of shifting microglial M1/M2 characteristics, especially the CD206 gene expression pattern between depressive and manic states. Further translational studies are needed to dig up the microglial roles in the underlying biological mechanisms of bipolar disorder.

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TNF-α from hippocampal microglia induces working memory deficits by acute stress in mice

Cited by 62 publications

References 34 publications

Donepezil suppresses intracellular Ca2+ mobilization through the PI3K pathway in rodent microglia

Donepezil suppresses intracellular Ca2+ mobilization through the PI3K pathway in rodent microglia

The Cholinergic System Modulates Memory and Hippocampal Plasticity via Its Interactions with Non-Neuronal Cells

Microglial CD206 Gene Has Potential as a State Marker of Bipolar Disorder

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