TY  - JOUR
AU  - Henning, Lukas
AU  - Antony, Henrike
AU  - Breuer, Annika
AU  - Müller, Julia
AU  - Seifert, Gerald
AU  - Audinat, Etienne
AU  - Singh, Parmveer
AU  - Brosseron, Frederic
AU  - Heneka, Michael T.
AU  - Steinhäuser, Christian
AU  - Bedner, Peter
TI  - Reactive microglia are the major source of tumor necrosis factor alpha and contribute to astrocyte dysfunction and acute seizures in experimental temporal lobe epilepsy
JO  - Glia
VL  - 71
IS  - 2
SN  - 0894-1491
CY  - Bognor Regis [u.a.]
PB  - Wiley-Liss
M1  - DZNE-2022-01566
SP  - 168 - 186
PY  - 2023
N1  - CC BY-NC-ND: https://creativecommons.org/licenses/by-nc-nd/4.0/
AB  -  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.
KW  - Mice
KW  - Animals
KW  - Humans
KW  - Epilepsy, Temporal Lobe: pathology
KW  - Astrocytes: pathology
KW  - Tumor Necrosis Factor-alpha
KW  - Microglia: pathology
KW  - Hippocampus: pathology
KW  - Seizures: pathology
KW  - Status Epilepticus: pathology
KW  - Kainic Acid: toxicity
KW  - Disease Models, Animal
KW  - Mice, Knockout
KW  - astrocyte (Other)
KW  - gap junction coupling (Other)
KW  - hippocampal sclerosis (Other)
KW  - microglia (Other)
KW  - temporal lobe epilepsy (Other)
KW  - tumor necrosis factor alpha (Other)
KW  - Tumor Necrosis Factor-alpha (NLM Chemicals)
KW  - Kainic Acid (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36373840
DO  - DOI:10.1002/glia.24265
UR  - https://pub.dzne.de/record/165273
ER  -