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Single nucleus RNA sequencing of hippocampal tissue from wildtype and SHIP1 conditional knockout mice at postnatal day 15.

ABSTRACT: This study corresponds to the single nucleus RNA sequencing (snRNAseq) analysis done as part of the manuscript "Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system" by Matera et al. INPP5D, which encodes the lipid phosphatase SHIP1, is one of the most common genes associated with the risk of Alzheimer’s disease and is enriched in microglia in the central nervous system. SHIP1 has been found to be highly expressed in plaque-associated microglia. However, how it regulates microglial function and influences brain physiology has been poorly investigated. In this study, we generated a snRNAseq dataset from the hippocampi of wildtype (WT) and conditional SHIP1 knockout (KO) mice at postnatal day 15. By predicting cell-cell communication, we found decreased neuronal interactions in KO mice, in line with results of synaptic loss in the rest of the manuscript.

ORGANISM(S): Mus musculus

PROVIDER: GSE264452 | GEO | 2025/04/28

REPOSITORIES: GEO

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Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system

Project description:INPP5D, which encodes the lipid phosphatase SHIP1, is one of the most common genes associated with the risk of Alzheimer’s disease and is enriched in microglia in the central nervous system. SHIP1 has been found to be highly expressed in plaque-associated microglia. However, how it regulates microglial function and influences brain physiology has been poorly investigated. Here we show that SHIP1 is not only enriched in microglia associated with amyloid beta plaques, but also in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that conditional knockout mice lacking microglial SHIP1 (cKO) display increased complement and synapse loss in the early postnatal brain. Additionally, SHIP1 KO microglia show reduced morphological complexity, altered transcriptional signatures, and abnormal synaptic pruning, which is dependent on the complement system. Single nucleus RNA-sequencing analysis of the entire hippocampus confirmed decreased interaction for synaptic structure-related pathways in both excitatory and inhibitory neurons. Importantly, cKO mice show cognitive defects in adulthood only when microglial SHIP1 is depleted at early postnatal days, but not when depleted at later stages. Finally, using CRISPR/Cas9 we generated human iPSC-derived microglia lacking SHIP1, and validated the increased engulfment of synaptic structures. Altogether, these findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling through the complement system in the early postnatal brain. Disrupting this process has lasting behavioral effects and may provide a link to vulnerability to neurodegeneration.

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Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system

Project description:INPP5D, which encodes the lipid phosphatase SHIP1, is one of the most common genes associated with the risk of Alzheimer’s disease and is enriched in microglia in the central nervous system. SHIP1 has been found to be highly expressed in plaque-associated microglia. However, how it regulates microglial function and influences brain physiology has been poorly investigated. Here we show that SHIP1 is not only enriched in microglia associated with amyloid beta plaques, but also in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that conditional knockout mice lacking microglial SHIP1 (cKO) display increased complement and synapse loss in the early postnatal brain. Additionally, SHIP1 KO microglia show reduced morphological complexity, altered transcriptional signatures, and abnormal synaptic pruning, which is dependent on the complement system. Single nucleus RNA-sequencing analysis of the entire hippocampus confirmed decreased interaction for synaptic structure related pathways in both excitatory and inhibitory neurons. Importantly, cKO mice show cognitive defects in adulthood only when microglial SHIP1 is depleted at early postnatal days, but not when depleted at later stages. Finally, using CRISPR/Cas9 we generated human iPSC-derived microglia lacking SHIP1, and validated the increased engulfment of synaptic structures. Altogether, these findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling through the complement system in the early postnatal brain. Disrupting this process has lasting behavioral effects and may provide a link to vulnerability to neurodegeneration.

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Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system

Project description:Microglial SHIP1 controls synaptic pruning in the developing hippocampus via the complement system

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