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Despite increasing evidence reporting the activation of pro\u2010inflammatory microglia as a cardinal event of NPC1 disease progression at symptomatic stages both in patients and preclinical models, how microglia cells respond to altered neurodevelopmental dynamics remains not completely understood. To gain an insight on this issue, we have characterized patterns of microglia activation in the early postnatal cerebellum and young adult olfactory bulb of the hypomorphic <jats:italic>Npc1<\/jats:italic><jats:sup><jats:italic>nmf164<\/jats:italic><\/jats:sup> mouse model. Previous evidence has shown that both these areas display a number of anomalies affecting neuron and glial cell proliferation and differentiation, which largely anticipate cellular changes and clinical signs, raising our interest on how microglia interplay to these changes. Even so, to separate the contribution of cues provided by the dysfunctional microenvironment we have also studied microglia isolated from mice of increasing ages and cultured in vitro for 1\u2009week. Our findings show that microglia of both cerebellum and olfactory bulb of <jats:italic>Npc1<\/jats:italic><jats:sup><jats:italic>nmf164<\/jats:italic><\/jats:sup> mice adopt an activated phenotype, characterized by increased cell proliferation, enlarged soma size and de\u2010ramified processes, as well as a robust phagocytic activity, in a time\u2010 and space\u2010specific manner. Enhanced phagocytosis associates with a profound remodeling of gene expression signatures towards gene products involved in chemotaxis, cell recognition and engulfment, including Cd68 and Trem2. These early changes in microglia morphology and activities are induced by region\u2010specific developmental anomalies that likely anticipate alterations in neuronal connectivity. As a proof of concept, we show that microglia activation within the granule cell layer and glomerular layer of the olfactory bulb of <jats:italic>Npc1<\/jats:italic><jats:sup><jats:italic>nmf164<\/jats:italic><\/jats:sup> mice is associated with shortfalls in fine odor discrimination.<\/jats:p>","DOI":"10.1002\/jcp.30909","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T18:00:37Z","timestamp":1667412037000},"page":"4563-4579","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The appearance of phagocytic microglia in the postnatal brain of Niemann Pick type C mice is developmentally regulated and underscores shortfalls in fine odor discrimination"],"prefix":"10.1002","volume":"237","author":[{"given":"Alessandro","family":"Rava","sequence":"first","affiliation":[{"name":"Division of Neuroscience, Department of Psychology University La Sapienza Rome Italy"},{"name":"PhD program in 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