Spared cognitive and social function following perinatal ablation of ATRX despite transient microglia dysregulation.

Mutations in the chromatin-remodelling factor ATRX cause syndromic intellectual disability (ID) and autism spectrum disorder (ASD), but the role of microglial ATRX in early brain development remains poorly understood. Here, we used a tamoxifen-inducible Cx3cr1-CreERT2 system to delete Atrx specifically in microglia during the first postnatal week. High recombination efficiency was achieved by one month of age; however, knockout efficiency declined by three months to approximately 20% in the cortex and 40% in the hippocampus, suggesting repopulation by wild-type microglia. ATRX-deficient microglia exhibit an increase in CD68-positive foci, greater ramification complexity, and enlarged cell volume, consistent with a reactive phenotype. Furthermore, we observed an elevated proportion of Ki67-positive proliferative microglia at both one and three months of age. To assess the functional consequences of these cellular alterations, we evaluated juvenile and adult ATRX microglial knockout (mi-KO) and control mice across a behavioural battery assessing anxiety-like behaviour, locomotion, learning and memory, social interaction, and sensory gating. No significant genotype-dependent differences were detected across these domains. Together, these findings indicate that perinatal loss of ATRX in microglia induces a reactive phenotype and turnover without measurable impacts on neurobehavioural outcomes, suggesting developmental resilience of neural circuits to transient microglial dysregulation.