Altered Brain Structure in an ATRX ‐Deficient Mouse Model of Autism Spectrum Disorder

Mutations in the ATRX gene are a primary cause of alpha-thalassemia intellectual disability X-linked (ATRX) syndrome, which is characterized by intellectual disability, autism, and a range of brain structural abnormalities, including microcephaly. We previously showed that mice with conditional ATRX ablation in forebrain excitatory neurons display deficits in fear memory and autism-related behaviors, with some effects exhibiting sexual dimorphism. In this study, we used high-resolution magnetic resonance imaging (MRI) to systematically characterize brain structural changes associated with these behavioral abnormalities. Whole-brain analysis revealed male-specific microcephaly, while subregional analysis identified significant reductions in hippocampal structures and increased volume of the caudal cortex in mutant animals of both sexes. We also identified structural alterations in regions retaining ATRX expression, such as the thalamus, midbrain, cerebellum, and several fiber tracts. These findings suggest that ATRX loss disrupts the coordinated development of interconnected brain regions. Overall, our results implicate impaired cortico-thalamic-cerebellar connectivity as a potential neural substrate underlying the autistic-like behaviors observed in this mouse model, providing new insights into the neurobiological basis of ATR-X syndrome.