Memory System Maladaptation Impairs CA1-Dependent Temporal Binding and Declarative Memory in the Cntnap2 Knockout Mouse Model of Autism

Growing evidence implicates the hippocampus in the pathophysiology of autism spectrum disorder, particularly in the domains of social interactions and cognition. Yet, the mechanisms driving hippocampal-dependent cognitive atypicalities in autism remain poorly defined. Here, we characterize how dysfunction of the CA1 subfield of the dorsal hippocampus (dCA1) impacts critical components of declarative memory. Using trace fear conditioning combined with in vivo fiber photometry in the Cntnap2 knockout mouse model of autism, we found that capabilities to bridge temporally distant stimuli, i.e. temporal binding capabilities, were reduced relative to wildtype mice. This impairment was associated with decreased dCA1 activity during temporal gaps. Using a relational/declarative memory task, we also revealed a deficit in flexible spatial memory, a preferential use of egocentric learning strategy. This unflexible learning strategy resulted from the imbalance between memory system activity, promoting frontostriatal-dependent procedural learning instead of dorsal dCA1/hippocampus-dependent relational/declarative memory. Overall, this study elucidates how memory systems are mistuned in the Cntnap2 knockout mouse model, opening new avenues for understanding and addressing atypical learning in autism.