Maladaptation of Memory Systems Impairs Dorsal CA1-Dependent Temporal Binding and Declarative Memory in The Cntnap2 Knockout Mouse Model of Autism

The CA1 region of the hippocampus plays a multifaceted role in cognitive functions related to temporal binding, spatial navigation, and social interactions. Growing evidence reports a role of the hippocampus in the pathophysiology of autism spectrum disorder, particularly in social interactions and cognitive domains. Yet, the mechanisms driving hippocampal-driven cognitive impairments remain poorly defined. Here, we characterized how dorsal CA1 dysfunction impacts the long term retention of temporally discontiguous events. We found that Cntnap2 knockout mice exhibit reduced temporal binding capabilities compared to controls, stemming from decreased dorsal CA1 activity during temporal gaps. We further demonstrate a deficit of the flexibility component of relational/declarative memory in Cntnap2 KO mice. This impairment was secondary to the use of a procedural learning strategy associated with the imbalance of memory systems, in favor of the activity of the frontal-striatal areas, instead of the hippocampus. This study offers deeper insights into how memory systems are mistuned in autism, opening new avenues for understanding and addressing atypical cognition in this condition.