Impaired removal of dying brain cells by microglia in Gpr34 deficient mice

GPR34, a G protein-coupled receptor present selectively in microglia and other myeloid cells, is highly expressed in homeostatic microglia but is downregulated in disease associated microglia (DAM) such as those found in Alzheimer’s disease brain. However, little is known about GPR34’s role in microglia function or brain development. Here, we studied Gpr34 knockout (KO) mice at postnatal 18-day (P18) and 3 months (3 mo) age. In the brains of P18 Gpr34 KO mice, there were elevated numbers of neurons, oligodendrocytes and microglia, many of which were IHC-positive for the cell death markers cleaved-caspase 3, phospho-RIP3, or annexin V. P18 KO animals showed a reduced localization of microglia in areas of high cell death, while the increased evidence of cell death way largely resolved in 3 mo animals. While the uptake of bacterial particles was not impacted ex-vivo, KO microglia showed increased intracellular accumulation of endogenous cargo, myelin basic protein (MBP) and synaptosomal-associated protein 25 (SNAP25), suggesting altered handling of apoptotic debris without a global phagocytic defect. Notably, transcriptomic analysis revealed persistent impact of immune pathways even at 3 months, at the stage where KO mice also displayed sustained hypolocomotion. Collectively, these results indicate that murine Gpr34 contributes to early clearance of dying cells and may influence a long-lasting impact on microglia state and behavior. Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-026-03777-4.