Abstract
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.
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All data generated or analyzed in this study are included in this published article.
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Acknowledgements
We are grateful to Drs. Vania Prado and Marco Prado for the Cx3Cr1ER mice, and for access to the Robarts Research Institute neurobehavioral core facility along with the guidance of the facility manager Matthew Cowan.
Funding
This work was supported by the Canadian Institutes for Health Research operating grant to N.G.B. (FRN#183661) and by BrainsCAN through the Canada First Research Excellence Fund. K.Y.M. received a Summer Studentship and a Graduate Studentship from the Department of Paediatrics at Western University, an Ontario Graduate Scholarship and the C. Allison Kingsley Research Grant from the Department of Psychiatry at Western University. S.S. received a Children’s Health Research Institute Postdoctoral award from the Children’s Health Foundation.
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K.Y.M. contributed to conceptualization, data curation, formal analysis, and writing - original draft and review & editing; M.P.O. contributed to data curation, formal analysis and manuscript editing; S.S contributed to conceptualization and data curation; J.W. contributed to data curation; N.G.B contributed to conceptualization, funding acquisition, supervision, writing original draft and review & editing.
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Mansour, K.Y., Pena-Ortiz, M.A., Wu, J. et al. Spared cognitive and social function following perinatal ablation of ATRX despite transient microglia dysregulation. Sci Rep (2026). https://doi.org/10.1038/s41598-026-41476-5
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DOI: https://doi.org/10.1038/s41598-026-41476-5
