Language-Relevant Auditory Processing in the Cntnap2 Knockout Mouse

Background:  The investigation of genetic variants that contribute to autism spectrum disorder (ASD) is critical for understanding the neurodevelopmental basis of the disorder. The gene contactin associated protein-like 2 (CNTNAP2) has been linked to both ASD and specific language impairment. CNTNAP2 is located on chromosome 7q35 and encodes a cell adhesion protein that regulates signal transmission at the synapse. It is directly regulated by FOXP2, a transcription factor associated with language development. Additionally, CNTNAP2 is highly expressed in language relevant cortical areas. To better understand the behavioral and biological mechanisms of ASD, a transgenic mouse model was recently generated with a genetic knockout of Cntnap2, the rodent homolog of CNTNAP2. Studies of this knockout model describe ASD-like symptoms, including poor social interactions, behavioral perseveration, and reduced vocalizations (Peñagarikano et al. 2011). However, language-relevant, low-level auditory processing in the knockout model has not previously been characterized. Recent evidence suggests that humans with ASD have impaired temporal auditory processing (Bhatara et al. 2013) and enhanced pitch discrimination (Eigsti & Fein 2013; Mottron et al. 2006; Bonnel et al. 2003), both features that may disrupt typical language development. That is, individuals with ASD show difficulty with some temporal aspects of auditory processing, but enhanced discrimination of spectral cues.

Objectives:  The aim of the current study was to assess language-relevant intermediate phenotypes in the Cntnap2knockout model, targeting rapid temporal auditory processing and pitch discrimination abilities. 

Methods:  Twenty-two male Cntnap2 knockout (KO) and 23 male wild type C57BL/6 (WT) mice were assessed. The groups were identical in age. A modified pre-pulse inhibition paradigm was used to examine attenuation of the acoustic startle response to a startle eliciting stimulus (SES) in the context of various auditory cues. Two acoustic tasks were performed. A “silent gap” task measured temporal aspects of auditory processing by examining the subjects’ ability to detect variable duration silent gaps within continuous white noise. In this task, the cue for the SES was a silent gap. An “embedded tone” task measured spectral characteristics of auditory processing by examining the subjects’ ability to detect brief changes in frequency embedded within a continuous background pure tone. In this task, the cue for the SES was a frequency change. 

Results:  KO mice exhibited significant deficits relative to WT in rapid auditory processing in the temporal silent gap task (F(1,40)=6.29, p=.016). However, KO mice exhibited significantly enhanced pitch discrimination in the spectral embedded tone task (F(1,40)=9.39, p=.004).

Conclusions:  The pattern of impairment and enhancement seen in the Cntnap2 KO mouse matches the pattern seen in humans with ASD. These findings suggest that CNTNAP2 may play a role in development of low-level auditory processing features that contribute to human language and that aberrant CNTNAP2 may be responsible for language atypicalities in individuals with ASD.