Pre-Attentive and Cognitive Sensory Processing in Rats Lacking the Autism Candidate Gene CNTNAP2

Background: Pre-attentive and cognitive processing of sensory information is necessary for appropriate interactions with our environment. In individuals with autism spectrum disorder (ASD), impairments in lower-level sensory filtering and processing can impact higher-order functions that rely on the ability to decipher complex sensory signals. For example, sensory disturbances have been suggested to contribute to social communication weakness in the autism population, with central auditory processing and audiovisual temporal acuity being linked to auditory hyper- and hypo- sensitivities and language deficits. However, at present, the neural basis for these behavioural deficits remains unresolved. Preclinical animal models could help to reveal the mechanisms of altered sensory processing if they can first show high face validity for ASD-related behavioral deficits.

Objectives: To assess both 1. sound intensity and 2. multisensory processing on the pre-attentive and cognitive level in rats lacking the autism candidate gene CNTNAP2 (Cntnap2^-/- rats) using translational behavioural paradigms.

Methods: In male and female adult Sprague-Dawley Cntnap2 homozygous knockout, heterozygous knockout, and wildtype rats, pre-attentive processing was examined utilizing the acoustic startle response (ASR; 20 ms, 110 dB SPL) and its modulation by a stimulus (i.e. prepulse) which occurred before the acoustic startle-eliciting stimulus. Prepulse conditions included an acoustic noise burst at varying intensities (A; 10 ms, 62 – 92 dB SPL in 3 dB steps), a visual LED flash (V; 10 ms, 70 lux), or a combined audiovisual stimulus (AV; 10 ms, 68 dB SPL, 70 lux). For cognitive testing, two-alternative forced choice, appetitive paradigms assessed the rats’ ability to discriminate the relative sound intensity of acoustic noise bursts (71 dB SPL – 89 dB SPL in 3 dB steps) or the relative timing (temporal order judgement – TOJ) of audiovisual stimuli (stimulus asynchronies used: A400V, A200V, A100V, AV, V100A, V200A, V400A) consistent with studies on humans. Moreover, discrimination training on sound intensity was conducted to determine the differential plasticity of pre-attentive and cognitive loudness processing.

Results: As expected, the Cntnap2^-/- rats exhibited a general impairment in prepulse inhibition of the ASR compared to age-matched wildtype controls. Interestingly, Cntnap2^-/- rats, like wildtypes, showed a greater level of prepulse inhibition when the audiovisual (AV) prepulse was presented compared to the unimodal (A or V) prepulse conditions; findings which indicate that the brainstem of knockout rats was still able to integrate auditory and visual stimuli. Cntnap2^-/- rats showed no deficit in loudness discrimination or temporal order perception. Upon training, genotypic differences arose in the plasticity of acoustic discriminations.

Conclusions: The general PPI deficit observed relates to research suggesting pathological sensory processing underpins the emergence of ASD-related phenotypes. While the audiovisual results are consistent with previous studies in the autistic population performing the TOJ task with simple flash-beep stimuli, the lack of differences in loudness discrimination appears contrary to reports of moderate sound intensities being reported as distressing. However, discrimination ability is not homologous to the objective perception of acoustic stimuli. Taken together, these results highlight the validity of Cntnap2^-/- rats as a preclinical model for studying sensory processing associated with ASD.