Characterizing The Auditory Processing Alterations At The Electrophysiological Neuronal Level In The Cntnap2-/- Rat Model Of Autism
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.