Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Allman, Brian L.

2nd Supervisor

Schmid, Susanne

Co-Supervisor

Abstract

The contactin-associated protein-like 2 gene, CNTNAP2, is a highly penetrant gene thought to play a role in the genetic etiology of neurodevelopmental disorders such as autism spectrum disorder (ASD). Despite its link to ASD, the field lacks a complete understanding of the role CNTNAP2 plays in the hallmarks of ASD: repetitive behaviours and abnormalities in social interaction, language, and sensory processing. Therefore, this thesis first examines if a loss-of-function mutation in the CNTNAP2 gene in the rat (SD-Cntnap2tm1Sage) is sufficient to cause alterations in social interactions, stereotypic behaviour, and sensory processing. Cntnap2 knockout rats showed deficits in sociability and social novelty, displayed repetitive circling and hyper-locomotion, and demonstrated exaggerated acoustic startle responses, an increased avoidance of sounds of moderate intensity, and a lack of rapid audiovisual temporal recalibration; indicating changes in sensory processing at both the pre-attentive and perceptual levels. Therefore, this study established the Cntnap2 knockout rat as an effective model to study the neural mechanisms underlying behavioural differences in ASD. Next, the role of Cntnap2 in acoustic stimulus processing was determined by examining the development of brainstem temporal processing, sensitivity, and sensory filtering using the auditory brainstem response (ABR) and acoustic startle response (ASR). Delayed maturation of the ABR and persistent differences in the ASR across age were identified in knockout rats. Since the sound-induced neural activity was found to be transmitted slower through the brainstem in juvenile Cntnap2-/- rats compared to wildtypes, the consequences of this altered development on cortical processing in adulthood were explored. Despite mature ABRs in adulthood, cortical auditory function remains altered. Specifically, immature cortical evoked potentials, delayed multi-unit response latencies, impaired temporal processing, and a pattern of hyper-excitability in both multi-unit and single-cell recordings were found. All these observations show striking parallels to disruptions reported in ASD. Overall, this work demonstrates that developmental disruptions in the Cntnap2 gene are associated with persistent changes in autism-associated behaviours, auditory evoked behaviour, and the neural circuitries responsible for processing acoustic information.

Summary for Lay Audience

Neurodevelopmental disorders, such as autism spectrum disorder (ASD), are caused by an interaction between a person’s genome and their environment during development. To study how different genes are related to autism, researchers study the behaviour and the brain of animal models with mutations in those genes. In this thesis, the contactin-associated protein-like 2 gene, Cntnap2, was studied using a rat model lacking a working version of this gene. Behaviours related to the diagnostic criteria of autism, namely social behaviour, restrictive and repetitive behaviour, and auditory sensory behaviours, were examined in these rats. We found the rats showed differences in these behaviours similar to what we see in autism. For example, they exhibited fewer social interactions, more repetitive behaviours, a greater response to startling sounds, and found moderately loud sounds more aversive. Because we know that the way the brain processes sounds is different in autism, in this thesis we also explored how the brain of the rats lacking a working Cntnap2 gene responds to sound stimuli. Similar to autistic individuals, we found that the Cntnap2 knockout rats’ brainstem auditory response was slower to mature. We also know that in ASD, and other language-related disorders, the cortical auditory response to sound appears immature and that the cortex cannot process rapidly presented sounds. We examined these characteristics in the rat’s auditory cortex and found a similar profile of immaturity. Since the Cntnap2 knockout rat model reflects ASD so well, it can now be used to explore the underlying cellular and molecular mechanisms through which Cntnap2 works to influence ASD-related behaviours and sound processing.

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