A key regulator of microglial physiology is TYROBP (aka DAP12), an adaptor protein that has been extensively studied in the context of age-related neurodegenerative diseases. However, little is known about its role in brain postnatal development. To investigate this, we generated a novel mouse model expressing mutant TYROBP with a disrupted signalling motif. Proteomic analysis of total brain lysates revealed dysregulations in synapse maturation-related functions. In addition, we found mild age- and brain region-specific differences in microglia density and volumes in the mutant TYROBP brains. Co-expressing TREM2, a cognate receptor of TYROBP, together with either wild-type or mutant TYROBP in HeLa cells, we observed unaltered TREM2-TYROBP interactions and subcellular localisation. However, synaptosomal uptake was significantly reduced in cells co-expressing mutant TYROBP. As these results could imply altered synaptic pruning with potentially life-long consequences, we examined mutant mice behaviour at 6 months of age and identified subtle impairments in males but not females compared with wild-type control animals. Together, our data reveal a role for TYROBP in postnatal brain development, with mild consequences on the behaviour of adult male mice.