A mouse model of ATRX deficiency with cognitive deficits and autistic traits

ABSTRACT ATRX is an ATP-dependent chromatin remodeling protein with essential roles in safeguarding genome integrity and modulating gene expression. Deficiencies in this protein cause ATR-X syndrome, a condition characterized by intellectual disability and an array of developmental abnormalities, including features of autism. Previous studies demonstrated that deleting ATRX in mouse forebrain excitatory neurons postnatally resulted in male-specific memory deficits. Here, we introduce a new model where ATRX is deleted at earlier embryonic stages, resulting in a broader spectrum of impairments, including contextual fear memory deficits, decreased anxiety, hyperactivity, as well as self-injurious and stereotyped behaviours. Sex-specific alterations were also observed, with males displaying heightened aggression and impaired sensory gating, while females exhibit social avoidance. Collectively, the findings indicate that early developmental abnormalities arising from ATRX deficiency in neurons contribute to of the presentation of autistic-like behaviours. Summary Statement Mice with embryonic loss of ATRX in excitatory neurons represent a clinically relevant model to study sexually dimorphic alterations in cognitive and autistic traits.