Investigating developmental outcomes of ATRX ablation in embryonic excitatory neurons
Abstract
Alpha-thalassemia intellectual disability X-linked (ATRX) is an ATP-dependent chromatin remodeling protein, and mutations in the ATRX gene are associated with ATR-X syndrome and autism spectrum disorder (ASD). Previous studies demonstrated that loss of ATRX in excitatory neurons in the postnatal forebrain leads to male-specific memory impairments without evidence of ASD features. It remained possible that an earlier inactivation of ATRX in neurons might yield a model to study ASD. To address this gap, we generated and characterized mice that lack ATRX expression starting at embryonic day 11, specifically in postmitotic excitatory neurons of the forebrain. Behavioural characterization of male and female conditional knockout (cKO) mice reveals ASD-like behaviors in adult mice of both sexes, although males display more extensive deficits than females. We observed significant morphological changes in the brain at one year of age, including increased cortical and decreased hippocampal volumes. Unexpectedly, alterations are seen in brain regions that retain ATRX expression, suggesting indirect effects of ATRX deletion in forebrain neurons on the development of other brain regions. Analysis of late embryonic cortical transcriptomes identified deficits related to translation and mitochondria in male and female Atrx cKO mice. By the second postnatal week, we found that the transcriptional profiles diverge between male and female Atrx cKO cortices. This included male-specific upregulation of genes related to the hedgehog pathway, cilia, and neuronal maturation, which coincided with a higher number of Ctip2+ neurons and increased synaptic density in deep cortical layers. We provide evidence that loss of ATRX in the male cortex triggers a precocious loss of epigenetic suppression of the neuronal maturation gene program, a change that is compensated for in the female cKO cortex. Overall, this study introduces a novel mouse model of ASD that exhibits sexual dimorphism in its presentation and highlights significant alterations in epigenetic and gene expression programming during a critical phase of brain development. Notably, the first two postnatal weeks are identified as a crucial period when female compensation mechanisms begin to emerge at the epigenetic and gene expression level.