Age-Dependent Effects of Loss of Contactin-Associated Protein-Like 2, an Autism-Associated Gene, on the Acquisition and Recall of Fear Memory

The contactin-associated protein-like 2 (Cntnap2) gene is relevant to autism spectrum disorder (ASD), which is associated with age-specific structural alterations in limbic brain regions. The Cntnap2 gene encodes for the contactin-associated protein-like 2 (CASPR2) protein, and CASPR2 protein levels are high in the amygdala, a limbic region that is essential for the processing of fear and anxiety. In humans, reduced levels of this protein arising from CNTNAP2 mutations could potentially account for the autism-associated increase in fear and anxiety. Here, we report the extent to which loss of CASPR2 in mice contributes to the development of fear- and anxiety-related behaviors. Pavlovian fear conditioning experiments revealed that loss of CASPR2 has age-dependent effects on the acquisition of fear memory, recall of both cue-evoked and context-related fear memory, and stability of cue-evoked fear memory. Additionally, data from the elevated zero maze suggest that CASPR2 deficiency contributes to anxiety-related behaviors, especially in juvenile (29-day old) mice. These are the first reports of age-dependent effects of CASPR2 deficiency on fear and anxiety-related behaviors, and they set the stage for a better understanding of developmental alterations of fear and anxiety in ASD.