Cntnap2 deletion in mice causes developmentally transient alterations in auditory processing and persistent startle hyperreactivity

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition often associated with auditory symptoms, including impairments in sound perception and hypersensitivity. These symptoms are thought to be partly due to the delayed development of the auditory brainstem, as evidenced through aberrant auditory brainstem responses (ABRs) and exaggerated startle responses in infants diagnosed with ASD. Loss-of-function mutations in CNTNAP2, a gene implicated in auditory processing and language development, are causally associated with ASD. Accordingly, knocking out Cntnap2 causes auditory brainstem impairments in rats; however, it is unknown if similar disruptions are observed in mice due to a possible conserved role of Cntnap2 in the auditory brainstem. To test this, we characterized the development of auditory processing, reactivity, and sensory filtering in juvenile and adult Cntnap2 knockout (KO) mice. We found that juvenile KO mice exhibited larger ABR wave III amplitudes and smaller wave IV widths, which normalized in adult mice, suggesting the possibility of transient hyperexcitability in the developing auditory brainstem. Additionally, our acoustic startle measurements revealed sex-specific phenotypes in which male KO mice exhibit an exaggerated startle response that persists into adulthood, while prepulse inhibition (PPI) remained generally intact in KO mice at both ages. These results demonstrate that loss of Cntnap2 in mice produces auditory brainstem abnormalities similar to rats, but causes species- and sex-specific effects on auditory reactivity, establishing the mouse model as a complementary animal model for investigating neural mechanisms underlying auditory dysfunction in ASD. Significance Statement Impairments in auditory processing are commonly reported amongst individuals diagnosed with autism spectrum disorder, but it is unclear how genetic risk factors can alter the brain circuits that underlie these auditory symptoms. Here, we used a mouse model with a high-confidence risk gene (CNTNAP2) to investigate how early auditory processing is impacted throughout development through both physiological and behavioural measures. We show that early auditory dysfunction is a conserved consequence of Cntnap2 loss early in development but normalized in adulthood, similar to the Cntnap2 knockout rat model. In contrast to the transient auditory brainstem response phenotype, we observed a sex-dependent alteration in auditory-evoked startle behaviour that persisted into adulthood. This work highlights the importance of investigating how altered sensory processing may contribute to the development of ASD-related behaviours and reinforces the need to consider sex as a biological variable when investigating neural mechanisms underlying neurodevelopmental disorders.