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Whereas it is very efficient in physiological conditions, it is impaired in mouse and human mesial temporal lobe epilepsy, and now we extend our studies to a model of progressive myoclonus epilepsy type 1 in mice lacking cystatin B (CSTB).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used confocal imaging and stereology\u2010based quantification of apoptosis and phagocytosis of the hippocampus of <jats:italic>Cstb<\/jats:italic> knockout (KO) mice, an in vitro model of phagocytosis and siRNAs to acutely reduce <jats:italic>Cstb<\/jats:italic> expression, and a virtual three\u2010dimensional (3D) model to analyze the physical relationship between apoptosis, phagocytosis, and active hippocampal neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Microglial phagocytosis was impaired in the hippocampus of <jats:italic>Cstb<\/jats:italic> KO mice at 1\u00a0month of age, when seizures arise and hippocampal atrophy begins. This impairment was not related to the lack of Cstb in microglia alone, as shown by in vitro experiments with microglial Cstb depletion. The phagocytosis impairment was also unrelated to seizures, as it was also present in <jats:italic>Cstb<\/jats:italic> KO mice at postnatal day 14, before seizures begin. Importantly, phagocytosis impairment was restricted to the granule cell layer and spared the subgranular zone, where there are no active neurons. Furthermore, apoptotic cells (both phagocytosed and not phagocytosed) in <jats:italic>Cstb<\/jats:italic>\u2010deficient mice were at close proximity to active cFos<jats:sup>+<\/jats:sup> neurons, and a virtual 3D model demonstrated that the physical relationship between apoptotic cells and cFos<jats:sup>+<\/jats:sup> neurons was specific for <jats:italic>Cstb<\/jats:italic> KO mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>These results suggest a complex crosstalk between apoptosis, phagocytosis, and neuronal activity, hinting that local neuronal activity could be related to phagocytosis dysfunction in <jats:italic>Cstb<\/jats:italic> KO mice. Overall, these data suggest that phagocytosis impairment is an early feature of hippocampal damage in epilepsy and opens novel therapeutic approaches for epileptic patients based on targeting microglial phagocytosis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16692","type":"journal-article","created":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T10:47:04Z","timestamp":1600339624000},"page":"2593-2608","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Microglial phagocytosis dysfunction in the dentate gyrus is related to local neuronal activity in a genetic model of epilepsy"],"prefix":"10.1111","volume":"61","author":[{"given":"Virginia","family":"Sierra\u2010Torre","sequence":"first","affiliation":[{"name":"Achucarro Basque Center for Neuroscience Science Park University of the Basque Country EHU\/UPV Leioa Spain"},{"name":"Department of Neuroscience University of the Basque Country UPV\/EHU Leioa 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