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 characterized how dysfunction of the CA1 subfield of the dorsal hippocampus drives critical components of declarative memory. Using trace fear conditioning in the Cntnap2 knockout mouse model of autism, we found that capabilities to retain the association of temporally distant stimuli ( i.e. temporal binding) were reduced relative to wildtype mice. Fiber photometry and optogenetic experiments demonstrated that reduced CA1 activity during temporal gaps underlies this impairment, linking CA1 dysfunction to a deficit of long-term memory retention in autism. Using a relational/declarative memory task, we also revealed a deficit in flexible spatial memory, and 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 CA1/hippocampus-dependent relational/declarative memory. Overall, this study establishes dorsal CA1 dysfunction as a circuit-level mechanism underlying cognitive inflexibility in autism, providing a neurobiological framework for hippocampal-dependent memory deficits in the condition.