Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Neuroscience
Supervisor
Schmid, Susanne
Abstract
The contactin-associated protein-like 2 (CNTNAP2) gene is an important developmental gene that, when mutated, is known to result in a developmental disorder with the core symptoms of autism spectrum disorder (ASD). In rodents, the deletion of Cntnap2 results in ASD-like phenotypes including hyperreactivity to sensory stimuli, particularly acoustic stimuli. Although auditory information processing is shown to be altered in Cntnap2-/- rats through behavioral tests, there is a lack of understanding of how Cntnap2 deletion affects neuronal and synaptic function in the brain areas responsible for relaying and processing auditory information. Therefore in this thesis, I explored the electrophysiological changes due to Cntnap2 deletion in multiple levels of the auditory system, from the peripheral brainstem level to higher processing at the cortical level. First, I aimed to understand the neuronal changes underlying the increased acoustic startle and reduced habituation in Cntnap2-/- rats, which is also commonly seen in people with ASD. As startle and its habituation involve synaptic plasticity in auditory and trigeminal afferents that innervate giant neurons located in the caudal pontine reticular nucleus (PnC), I hypothesized this synaptic plasticity would be impaired in Cntnap2-/- rats. Indeed, I found a reduction in synaptic depression, which is likely the mechanism for disrupted habituation in Cntnap2-/- rats. Next, changes in the excitatory neurons in the auditory cortex were assessed in Cntnap2-/- rats at multiple developmental timepoints, in order to understand how Cntnap2 deletion impacts the developmental trajectory of higher order auditory processing. Cntnap2-/- neurons were hyperexcitable at the juvenile age (post-natal day 18-21), but most differences were ameliorated by the adult age. Finally, to assess the environmental effect on the penetrance of Cntnap2 deletion, I employed different breeding strategies where the wildtype and Cntnap2-/- rats were obtained through homozygous breeding (Cntnap2-/- x Cntnap2-/-) or heterozygous breeding (Cntnap2+/- x Cntnap2+/-), which influence the rearing environment. Auditory cortical neurons in adult Cntnap2-/- rats from homozygous breeding were more immature and hyperexcitable than those from heterozygous breeding. Overall the findings in my thesis show that Cntnap2 deletion results in neuronal alterations at multiple levels of auditory processing that likely underly the behavioral changes like increased reactivity and reduced habitation to sound. They also show that these neuronal properties are malleable through environmental changes during development.
Summary for Lay Audience
Autism spectrum disorder (ASD) is a complex developmental disorder that is caused by genetic and/or environmental factors. Certain genes are highly important for early brain development, and when they are mutated, this can result in the onset of ASD. One such gene is the contactin-associated protein-like 2 (CNTNAP2). Importantly, this gene is not exclusive to humans, but is also present in other animals such as rodents. The deletion of Cntnap2 in rats causes autism-like symptoms, including highly exaggerated responses to sounds. Sound is processed in several areas of the brain, starting from the ear to the brainstem, from where it is sent to higher brain areas (i.e. auditory cortex), which allows us to consciously perceive the sounds. Given the importance of Cntnap2 for sound processing, in my thesis I was interested in how the deletion of Cntnap2 impacts the brain areas responsible for processing sounds. I first looked at the brainstem areas that relay sound information, since Cntnap2 knockout rats startle more to sounds. Moreover when the sounds are repeated multiple times, the startle response is typically reduced in people and rats – they get used to the sound – but instead the knockout rats continue to startle strongly. Areas in the brainstem are thought to play a major role in startle, as it is a quick reflexive behaviour, and the brainstem neurons directly activate the startle response. I found there were changes in the brainstem areas involved in startle in the Cntnap2 knockout rats, and these changes likely lead to the increased startle behaviours. Next I looked at a higher sound processing area, the auditory cortex, and found that in Cntnap2 knockout rats, brain activity was faster in young animals but was normalized in adult animals. Moreover I found that the environment in which the Cntnap2 knockout rats were reared also affected the activity in the auditory cortex, such that knockout rats that were reared by knockout dams continued to have faster and immature brain activity in the adult age. Overall my thesis found that brain areas involved in sound processing are changed at multiple levels of the brain in the Cntnap2 knockout rats, and that these changes can be influenced by the environment of upbringing. These findings help us better understand how changes in sound processing in ASD occur at the brain level.
Recommended Citation
Mann, Rajkamalpreet S., "Characterizing The Auditory Processing Alterations At The Electrophysiological Neuronal Level In The Cntnap2-/- Rat Model Of Autism" (2024). Electronic Thesis and Dissertation Repository. 10201.
https://ir.lib.uwo.ca/etd/10201
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