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Abstract
BackgroundAlpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in excitatory neurons of the forebrain and performed a battery of behavioural assays that assess autistic-like behaviours.MethodsMale and female mice with a postnatal conditional ablation of ATRX were generated using the Cre/lox system under the control of the αCaMKII gene promoter. These mice were tested in a battery of behavioural tests that assess autistic-like features. We utilized paradigms that measure social behaviour, repetitive, and stereotyped behaviours, as well as sensory gating. Statistics were calculated by two-way repeated measures ANOVA with Sidak’s multiple comparison test or unpaired Student’s t tests as indicated.ResultsThe behaviour tests revealed no significant differences between Atrx-cKO and control mice. We identified sexually dimorphic changes in odor habituation and discrimination; however, these changes did not correlate with social deficits.ConclusionThe postnatal knockout of Atrx in forebrain excitatory neurons does not lead to autism-related behaviours in male or female mice.
Highlights
Alpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism susceptibility gene that encodes a chromatin remodeler
Dimorphic olfaction differences in Alpha-thalassemia mental retardation (Atrx)-Conditional knockout (cKO) mice As olfactory impairments can confound the interpretation of other tests, especially social behaviour assays, we first wanted to address whether the loss of Atrx in excitatory neurons of the forebrain alters olfaction in male and female mice
There was no significant difference in the overall amount of time spent sniffing the odors throughout the test between AtrxcKOFEMALE and CtrlFEMALE mice
Summary
Alpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in excitatory neurons of the forebrain and performed a battery of behavioural assays that assess autistic-like behaviours. Mutations in the ATRX gene are associated with an intellectual disability syndrome referred to as ATRXsyndrome, characterized by autistic-like behaviours in addition to cognitive deficits, intellectual disabilities, and developmental delays [11]. Autistic carriers of rare mutations in ATRX have been discovered and missense variants in ATRX have been identified in male ASD patients. Female carriers of ATRX mutations experience skewed X-inactivation, and as a result, are asymptomatic [12,13,14,15,16,17,18]
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