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Using a mouse model closely recapitulating key alterations of chronic human MTLE with hippocampal sclerosis, here we asked whether death of astrocytes contributes to the initiation of the disease and investigated potential underlying molecular mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Antibody staining was combined with confocal imaging and semiquantitative real\u2010time polymerase chain reaction analysis to identify markers of different cellular death mechanisms between 4\u00a0h and 3\u00a0days after epilepsy induction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four hours after kainate\u2010mediated induction of status epilepticus (SE), we found a significant reduction in the density of astrocytes in the CA1 stratum radiatum (SR) of the ipsilateral hippocampus. This reduction was transient, as within the next 3\u00a0days, astrocyte cell numbers recovered to the initial values, which was accompanied by enhanced proliferation. Four hours after SE induction, a small proportion of astrocytes in the ipsilateral CA1 SR expressed autophagy\u2010related genes and proteins, whereas we did not find astrocytes positive for cleaved caspase 3 or terminal deoxynucleotide transferase\u2013mediated deoxyuridine triphosphate nick\u2010end labeling, ruling out apoptosis\u2010related astrocytic death. Importantly, at the same early time point post\u2010SE, many astrocytes in the ipsilateral CA1 SR showed strong expression of genes encoding pro\u2010necroptosis factors, including receptor\u2010interacting protein kinase 3 (<jats:italic>RIPK3<\/jats:italic>) and mixed lineage kinase domain\u2010like protein (<jats:italic>MLKL<\/jats:italic>). Phosphorylation of MLKL (pMLKL), formation of necrosome complexes composed of RIPK3 and pMLKL, and translocation of pMLKL to the nucleus and to the plasma membrane were often observed in astrocytes of the ipsilateral hippocampus 4\u00a0h post\u2010SE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>The present study revealed that astrocytes die shortly after induction of SE. Our expression data and immunohistochemistry suggest that necroptosis and autophagy contribute to astrocytic death. These findings help to better understand how dysfunctional and pathological remodeling of astrocytes contributes to the initiation of temporal lobe epilepsy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16910","type":"journal-article","created":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T21:55:50Z","timestamp":1620338150000},"page":"1569-1583","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Cell death of hippocampal CA1 astrocytes during early epileptogenesis"],"prefix":"10.1111","volume":"62","author":[{"given":"Zhou","family":"Wu","sequence":"first","affiliation":[{"name":"Institute of Cellular Neurosciences Medical Faculty University of Bonn Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tushar","family":"Deshpande","sequence":"additional","affiliation":[{"name":"Institute of Cellular Neurosciences Medical Faculty University of Bonn Bonn Germany"},{"name":"Institute of 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