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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)\u03b1 and contribute to astrocyte dysfunction and severity of <jats:italic>status epilepticus<\/jats:italic> (SE). Immunohistochemical analyses revealed pronounced and persistent microglia reactivity, which already started 4\u2009h after KA\u2010induced 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\u2010specific inducible TNF\u03b1 knockout mice we identified microglia as the major source of TNF\u03b1 during early epileptogenesis. Importantly, microglia\u2010specific TNF\u03b1 knockout prevented SE\u2010induced gap junction uncoupling in astrocytes. Continuous telemetric EEG recordings revealed that during the first 4\u2009weeks after SE induction, microglial TNF\u03b1 did not significantly contribute to spontaneous generalized seizure activity. Moreover, the absence of microglial TNF\u03b1 did not affect the development of hippocampal sclerosis but attenuated gliosis. 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