Epileptogenesis due to glia-mediated synaptic scaling

Savin, Cristina; Triesch, Jochen; Meyer‐Hermann, Michael

doi:10.1098/rsif.2008.0387

Cited by 48 publications

(35 citation statements)

References 42 publications

(69 reference statements)

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“…The encephalitis in the TNF-transgenic mice has most likely also increased the risk for seizures by altering excitability of neurons or neuromodulatory responses as shown for other seizure models [4], [6], [13], [14], [15], [18], [63]. There is increasing evidence that cytokines such as TNF can interfere with the excitability of neurons by mediating synaptic scaling, e.g.…”

Section: Discussionmentioning

confidence: 98%

TNF-Overexpression in Borna Disease Virus-Infected Mouse Brains Triggers Inflammatory Reaction and Epileptic Seizures

et al. 2012

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Proinflammatory state of the brain increases the risk for seizure development. Neonatal Borna disease virus (BDV)-infection of mice with neuronal overexpression of tumor necrosis factor-α (TNF) was used to investigate the complex relationship between enhanced cytokine levels, neurotropic virus infection and reaction pattern of brain cells focusing on its role for seizure induction. Viral antigen and glial markers were visualized by immunohistochemistry. Different levels of TNF in the CNS were provided by the use of heterozygous and homozygous TNF overexpressing mice. Transgenic TNF, total TNF (native and transgenic), TNF-receptor (TNFR1, TNFR2), IL-1 and N-methyl-D-aspartate (NMDA)-receptor subunit 2B (NR2B) mRNA values were measured by real time RT-PCR. BDV-infection of TNF-transgenic mice resulted in non-purulent meningoencephalitis accompanied by epileptic seizures with a higher frequency in homozygous animals. This correlated with lower weight gain, stronger degree and progression of encephalitis and early, strong microglia activation in the TNF-transgenic mice, most obviously in homozygous animals. Activation of astroglia could be more intense and associated with an unusual hypertrophy in the transgenic mice. BDV-antigen distribution and infectivity in the CNS was comparable in TNF-transgenic and wild-type animals. Transgenic TNF mRNA-expression was restricted to forebrain regions as the transgene construct comprised the promoter of NMDA-receptor subunit2B and induced up-regulation of native TNF mRNA. Total TNF mRNA levels did not increase significantly after BDV-infection in the brain of transgenic mice but TNFR1, TNFR2 and IL-1 mRNA values, mainly in the TNF overexpressing brain areas. NR2B mRNA levels were not influenced by transgene expression or BDV-infection. Neuronal TNF-overexpression combined with BDV-infection leads to cytokine up-regulation, CNS inflammation and glial cell activation and confirmed the presensitizing effect of elevated cytokine levels for the development of spontaneous epileptic seizures when exposed to additional infectious noxi.

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Section: Discussionmentioning

confidence: 98%

TNF-Overexpression in Borna Disease Virus-Infected Mouse Brains Triggers Inflammatory Reaction and Epileptic Seizures

et al. 2012

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“…22,23 TNF-a can also increase the risk of seizures. 24 In rodents, status epilepticus elevates hippocampal cytokine concentrations. [16][17][18][19][20] Cytokine concentrations are elevated in human epileptic tissue.…”

Section: Discussionmentioning

confidence: 99%

Refractory Epilepsy Associated With Microglial Activation

et al. 2011

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MAP is prevalent in resected human epilepsy tissue. Failure to down-regulate MAP contributes to chronic neuronal hyperexcitability. We hypothesize that MAP initiates a cycle of inflammation-induced seizures and seizure-induced inflammation. Microglia-driven epilepsy may be a primary pathogenic process in a small number of cases, as suggested by the pathology and therapeutic response in our patient, but may contribute to epileptogenesis in many more.

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“…The microglia may contribute to plasticity through diffusible factors which can modulate synaptic strength [for example studies have shown that TNF-alpha increases surface expression of AMPA receptors in the synapse (Beattie et al, 2002; Savin et al, 2009; Stellwagen and Malenka, 2006)], can regulate potassium and calcium (Beck et al, 2008; Kofuji and Newman, 2004), and secrete neurotrophins which may aid injured neurons in recovery from the initial epileptic event (Miwa et al, 1997; Nakajima et al, 2001a). In the case of the mice used in this study, upon ablation of functional microglia, which would normally phagocytose necrotic neurons (and other necrotic or apoptotic neighboring cells and cell debris), plasticity of surviving neurons and glia could indeed be altered, and manifest itself as early handling-induced seizures or lack of recovery from acute seizures.…”

Section: Discussionmentioning

confidence: 99%

Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice

Mirrione

Konomos

Gravanis

et al. 2010

Neurobiology of Disease

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Activated microglia have been associated with neurodegeneration in patients and in animal models of Temporal Lobe Epilepsy (TLE), however their precise functions as neurotoxic or neuroprotective is a topic of significant investigation. To explore this, we examined the effects of pilocarpine induced seizures in transgenic mice where microglia/macrophages were conditionally ablated. We found that unilateral ablation of microglia from the dorsal hippocampus did not alter acute seizure sensitivity. However, when this procedure was coupled with lipopolysaccharide (LPS) preconditioning (1 mg/kg given 24 hours prior to acute seizure), we observed a significant pro-convulsant phenomenon. This effect was associated with lower metabolic activation in the ipsilateral hippocampus during acute seizures, and could be attributed to activity in the mossy fiber pathway. These findings reveal that preconditioning with LPS 24 hours prior to seizure induction may have a protective effect which is abolished by unilateral hippocampal microglia/macrophage ablation.

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Epileptogenesis due to glia-mediated synaptic scaling

Cited by 48 publications

References 42 publications

TNF-Overexpression in Borna Disease Virus-Infected Mouse Brains Triggers Inflammatory Reaction and Epileptic Seizures

TNF-Overexpression in Borna Disease Virus-Infected Mouse Brains Triggers Inflammatory Reaction and Epileptic Seizures

Refractory Epilepsy Associated With Microglial Activation

Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice

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