Microglial lipid phosphatase SHIP1 limits complement-mediated synaptic pruning in the healthy developing hippocampus

The gene inositol polyphosphate-5-phosphatase D (INPP5D), which encodes the lipid phosphatase SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1), is associated with the risk of Alzheimer’s disease (AD). How it influences microglial function and brain physiology is unclear. Here, we showed that SHIP1 was enriched in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that mice conditionally lacking microglial SHIP1 displayed increased complement and synapse loss in the early postnatal brain. SHIP1-deficient microglia showed altered transcriptional signatures and abnormal synaptic pruning that was dependent on the complement system. Mice exhibited cognitive defects in adulthood only when microglial SHIP1 was depleted early postnatally but not at later stages. Induced pluripotent stem cell (iPSC)-derived microglia lacking SHIP1 also showed increased engulfment of synaptic structures. These findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling in the healthy developing brain. Disrupting this process has lasting behavioral effects and may be linked to vulnerability to neurodegeneration. [Display omitted] •Inpp5d is expressed in microglia during early brain development•SHIP1-deficient microglia show enhanced phagocytic activity and complement expression•Deleting Inpp5d in microglia in the developing brain increases synaptic pruning•Developmental, but not adult, Inpp5d deletion affects adult cognitive function Inpp5d, which encodes the lipid phosphatase SHIP1, is a risk gene for Alzheimer’s disease, but its role in brain development has been poorly studied. Matera, Compagnion et al. demonstrate that Inpp5d is expressed in microglia during early postnatal brain development, where it limits synaptic pruning in a complement-dependent manner, and that its perturbation during brain development has long-lasting effects on cognitive function.