Effects of a postnatalAtrxconditional knockout in neurons on autism-like behaviours in male and female mice

Abstract

24Background: Alpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism 25 susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X 26 intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) 27 patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours 28 are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in 29 excitatory neurons of the forebrain and performed a battery of behavioural assays that assess 30 autistic-like behaviours. 31Methods: Male and female mice with a postnatal conditional knockout of Atrx were tested in a 32 battery of behavioural tests that assess autistic features. We utilized paradigms that measure social 33 behaviour, repetitive and stereotyped behaviours, as well as sensory gating. Statistics were 34 calculated by two-way repeated measures ANOVA with Sidak's multiple comparison test or 35 unpaired Student's T-tests as indicated. 36Results: The behaviour tests revealed no significant differences between Atrx-cKO and control 37 mice. We identified sexually dimorphic changes in odor habituation and discrimination; however, 38 these changes did not correlate with social deficits. We additionally observed sex-specific 39 differences in sociability, vertical episodes, and acoustic startle response when results were 40 analyzed by sex. 41 Conclusion: The postnatal knockout of Atrx in forebrain excitatory neurons does not lead to 42 autism-related behaviours in male or female mice.43 44 Keywords: autism spectrum disorder, ATRX, sex differences, social behaviours, repetitive 45 behaviours, startle response, genetically engineered mice, Cre/loxP system 46 Background 47 Autism spectrum disorder (ASD) is a behaviourally defined condition characterized by 48 deficits in social and communicative abilities, impaired sensory gating, as well as the presence of 49 stereotyped behaviours (1,2). Recent work has highlighted the important contribution of de novo 50 variants and inherited copy number variants in ASD, confirming a strong genetic component of 51 this disease (1-3). Numerous autism susceptibility genes have been identified and shown to share 52 commonalities in synaptic, transcriptional, and epigenetic mechanisms (4-6). Mouse models have 53typically been used to investigate the behavioural implications of genetic mutations associated 54 with ASD (7,8). However, these studies often omit the investigation of the sex-specific effects of 55 these genetic mutations, limiting the potential translational applications. In the general population, 56 ASD occurs at a 4:1 male:female ratio, highlighting the need to study the outcome of genetic 57 mutations in both male and female model systems (1,2). 58In this study, we describe the impact of targeted inactivation of Atrx in glutamatergic 59 neurons on behaviours related to autism in male and female mice. ATRX belongs to the SWI/SNF 60 family of chromatin remodeling factors (9,10). Mutations in ...