Functional Loss of Cntnap2 in the Rat Leads to Autism-related Alterations in Behaviour and Auditory Processing

Kaela Elizabeth Scott, The University of Western Ontario

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-Cntnap2^tm1Sage) 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.