Journal Article

DZNE-2022-01566

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Reactive microglia are the major source of tumor necrosis factor alpha and contribute to astrocyte dysfunction and acute seizures in experimental temporal lobe epilepsy

Henning, L. ; Antony, H. ; Breuer, A.Extern* ; Müller, J. ; Seifert, G. ; Audinat, E. ; Singh, P. ; Brosseron, F.DZNE* ; Heneka, M. T.Extern* ; Steinhäuser, C. ; Bedner, P.

2023
Wiley-Liss Bognor Regis [u.a.]

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Please use a persistent id in citations: doi:10.1002/glia.24265

Abstract: 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.

Keyword(s): Mice (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Epilepsy, Temporal Lobe: pathology (MeSH) ; Astrocytes: pathology (MeSH) ; Tumor Necrosis Factor-alpha (MeSH) ; Microglia: pathology (MeSH) ; Hippocampus: pathology (MeSH) ; Seizures: pathology (MeSH) ; Status Epilepticus: pathology (MeSH) ; Kainic Acid: toxicity (MeSH) ; Disease Models, Animal (MeSH) ; Mice, Knockout (MeSH) ; astrocyte ; gap junction coupling ; hippocampal sclerosis ; microglia ; temporal lobe epilepsy ; tumor necrosis factor alpha ; Tumor Necrosis Factor-alpha ; Kainic Acid

Note: CC BY-NC-ND: https://creativecommons.org/licenses/by-nc-nd/4.0/

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Contributing Institute(s):

1. Interventional Trials and Biomarkers in Neurodegenerative Diseases (AG Heneka1 ; AG Heneka 1)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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