Spared cognitive and social function following perinatal ablation of ATRX despite transient microglia dysregulation
Mansour, K. Y.; Shafiq, S.; Berube, N. G.
Show abstract
Mutations in the chromatin-remodelling factor ATRX underlie syndromic ID and ASD, yet the contribution of microglial ATRX to early brain development remains unknown. We used a tamoxifen-inducible Cx3cr1-CreERT2 system to delete Atrx in microglia during the first postnatal week, achieving >90% recombination at one month of age. At both one and three months, ATRX-null microglia displayed a sustained increase in CD68-positive phagocytic foci and in Ki67+ proliferative microglia, but an unexpected [~]20% reduction in microglial density, despite only modest evidence of caspase-3-mediated apoptosis. A comprehensive behavioural battery conducted between three and six months revealed normal anxiety, locomotion, learning, memory, social interaction and sensory gating, coinciding with a decline in knockout efficiency to [~]45% in cortex and [~]75% in hippocampus, suggestive of microglial repopulation by ATRX-expressing cells. These findings demonstrate that perinatal loss of ATRX drives chronic microglial reactivity and turnover with no discernable effects on neurobehaviours, suggesting a developmental resilience of neural circuits to transient microglial dysregulation.
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