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Thesis Format

Integrated Article

Degree

Master of Science

Program

Anatomy and Cell Biology

Supervisor

Bérubé, Nathalie G.

Abstract

Mutations in ATRX, which encodes a chromatin remodeling protein, have been identified in patients with autism and are associated with ATR-X syndrome, a genetic disorder characterized by cognitive deficits, developmental delays, and autistic-like behaviour. Despite the relationship between ATRX and autism, it is not yet known how mutations lead to autistic behaviour. To investigate this relationship, we generated two mouse models displaying distinct timing of Atrx inactivation in forebrain excitatory neurons. With these models, we performed behavioural paradigms to assess behaviour related to autism. Behavioural testing revealed that the conditional deletion of Atrx in differentiated forebrain neurons during embryogenesis leads to aggressive social behaviour, overgrooming stereotypies, and an exaggerated startle response in male mice. However, these autistic-like traits were not observed after a postnatal deletion of Atrx in forebrain neurons. We conclude that neuronal ATRX is required at early stages of forebrain development to suppress autistic-like behaviour in male mice.

Summary for Lay Audience

ATRX is a protein that alters the way DNA is packaged in the cell during various cellular processes that are important for proper development. Mutations that reduce ATRX activity cause ATR-X syndrome, a genetic disorder that presents with cognitive impairments, various developmental delays, and autistic-like behaviour. Additionally, mutations in the ATRX gene have been identified in patients with autism spectrum disorder. Despite this relationship between ATRX and autism, it is not yet known how mutations in ATRX ultimately result in autistic behaviour. To begin to address this question, we generated two mouse models in which Atrx was deleted in the cells of the brain that transmit information, called neurons, at distinct developmental time points - either in the embryo or several weeks after birth. We then investigated if either of these mouse models display behaviour related to autism by performing behavioural tests that assess sociability, repetitive and stereotyped behaviour, and startle response to sound. Although our group previously identified learning and memory impairments in mice with Atrx inactivation in neurons beginning ~20 days after birth, we did not detect any autistic-like behaviour. However, early inactivation of Atrx in neurons in the embryo resulted in behaviour that is considered to be “autistic-like” in mice. Specifically, male mice were aggressive toward other mice and handlers, exhibited excessive self-grooming, and an exaggerated response to sound. Overall, we conclude that only an early disruption in Atrx gene function in neurons can cause autistic-like behaviour.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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