Learning Delays in a Mouse Model of Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder with core symptoms of atypical social interactions and repetitive behaviors. It has also been reported that individuals with ASD have difficulty with multisensory integration, and this may disrupt higher-order cognitive abilities such as learning and social communication. Impairments in the integration of sensory information could in turn reflect diminished cross-modal white matter connectivity. Moreover, the genetic contribution in ASD appears to be strong, with heritability estimates as high as 90%. However, no single gene has been identified, and over 100 risk genes have been reported. One of these genes -- contactin-associated-like-protein 2 (CNTNAP2) -- was first associated with Specific Language Impairment, and more recently has been linked to ASD. CNTNAP2 encodes a cell adhesion protein regulating synaptic signal transmission. To better understand the behavioral and biological underlying mechanisms of ASD, a transgenic mouse model was created with a genetic knockout (KO) of the rodent homolog Cntnap2. Initial studies of this mouse found poor social interactions, behavioral perseveration, and reduced vocalizations -- all strongly resembling the human symptoms. Cntnap2 KO mice also show abnormalities in myelin formation, consistent with a hypo-connectivity model of ASD. The current study was designed to further assess the behavioral phenotype of this mouse model, with a focus on learning and memory. Cntnap2 KO and wild-type mice were tested on a 4/8 radial arm water maze for 14 consecutive days. Average total, working memory, total reference memory, initial reference memory, repeated reference memory errors and average turn angle on the 4/8 radial arm maze were independently assessed using a 2 x 14 repeated measures ANOVA. Results showed that Cntnap2 KO mice exhibited significant deficits in working and reference memory during the acquisition period of the task. During the retention period (i.e., after an asymptote in errors), Cntnap2 KO mice performed comparably to wild-type mice. These findings suggest that CNTNAP2 may play an underlying role in the development of neural systems important to learning and cross-modal integration, and disruption of this function could be associated with delayed learning in ASD