000165273 001__ 165273
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000165273 0247_ $$2doi$$a10.1002/glia.24265
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000165273 037__ $$aDZNE-2022-01566
000165273 041__ $$aEnglish
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000165273 1001_ $$aHenning, Lukas$$b0
000165273 245__ $$aReactive microglia are the major source of tumor necrosis factor alpha and contribute to astrocyte dysfunction and acute seizures in experimental temporal lobe epilepsy
000165273 260__ $$aBognor Regis [u.a.]$$bWiley-Liss$$c2023
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000165273 520__ $$a Extensive microglia reactivity has been well described in human and experimental temporal lobe epilepsy (TLE). To date, however, it is not clear whether and based on which molecular mechanisms microglia contribute to the development and progression of focal epilepsy. Astroglial gap junction coupled networks play an important role in regulating neuronal activity and loss of interastrocytic coupling causally contributes to TLE. Here, we show in the unilateral intracortical kainate (KA) mouse model of TLE that reactive microglia are primary producers of tumor necrosis factor (TNF)α and contribute to astrocyte dysfunction and severity of status epilepticus (SE). Immunohistochemical analyses revealed pronounced and persistent microglia reactivity, which already started 4 h after KA-induced SE. Partial depletion of microglia using a colony stimulating factor 1 receptor inhibitor prevented early astrocyte uncoupling and attenuated the severity of SE, but increased the mortality of epileptic mice following surgery. Using microglia-specific inducible TNFα knockout mice we identified microglia as the major source of TNFα during early epileptogenesis. Importantly, microglia-specific TNFα knockout prevented SE-induced gap junction uncoupling in astrocytes. Continuous telemetric EEG recordings revealed that during the first 4 weeks after SE induction, microglial TNFα did not significantly contribute to spontaneous generalized seizure activity. Moreover, the absence of microglial TNFα did not affect the development of hippocampal sclerosis but attenuated gliosis. Taken together, these data implicate reactive microglia in astrocyte dysfunction and network hyperexcitability after an epileptogenic insult.
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000165273 650_7 $$2Other$$aastrocyte
000165273 650_7 $$2Other$$agap junction coupling
000165273 650_7 $$2Other$$ahippocampal sclerosis
000165273 650_7 $$2Other$$amicroglia
000165273 650_7 $$2Other$$atemporal lobe epilepsy
000165273 650_7 $$2Other$$atumor necrosis factor alpha
000165273 650_7 $$2NLM Chemicals$$aTumor Necrosis Factor-alpha
000165273 650_7 $$0SIV03811UC$$2NLM Chemicals$$aKainic Acid
000165273 650_2 $$2MeSH$$aMice
000165273 650_2 $$2MeSH$$aAnimals
000165273 650_2 $$2MeSH$$aHumans
000165273 650_2 $$2MeSH$$aEpilepsy, Temporal Lobe: pathology
000165273 650_2 $$2MeSH$$aAstrocytes: pathology
000165273 650_2 $$2MeSH$$aTumor Necrosis Factor-alpha
000165273 650_2 $$2MeSH$$aMicroglia: pathology
000165273 650_2 $$2MeSH$$aHippocampus: pathology
000165273 650_2 $$2MeSH$$aSeizures: pathology
000165273 650_2 $$2MeSH$$aStatus Epilepticus: pathology
000165273 650_2 $$2MeSH$$aKainic Acid: toxicity
000165273 650_2 $$2MeSH$$aDisease Models, Animal
000165273 650_2 $$2MeSH$$aMice, Knockout
000165273 7001_ $$aAntony, Henrike$$b1
000165273 7001_ $$0P:(DE-2719)9000501$$aBreuer, Annika$$b2$$udzne
000165273 7001_ $$aMüller, Julia$$b3
000165273 7001_ $$aSeifert, Gerald$$b4
000165273 7001_ $$aAudinat, Etienne$$b5
000165273 7001_ $$aSingh, Parmveer$$b6
000165273 7001_ $$0P:(DE-2719)2810593$$aBrosseron, Frederic$$b7$$udzne
000165273 7001_ $$0P:(DE-2719)2000008$$aHeneka, Michael T.$$b8$$udzne
000165273 7001_ $$00000-0003-2579-8357$$aSteinhäuser, Christian$$b9
000165273 7001_ $$00000-0003-0090-7553$$aBedner, Peter$$b10
000165273 773__ $$0PERI:(DE-600)1474828-9$$a10.1002/glia.24265$$gp. glia.24265$$n2$$p168 - 186$$tGlia$$v71$$x0894-1491$$y2023
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