Developmental CA2 perineuronal net reduction restores social memory in Shank3 mutant mice

Individuals with Autism Spectrum Disorder (ASD) and related neurodevelopmental conditions, like Phelan-McDermid syndrome (PMDS), exhibit social recognition deficits. Shank3B knockout (KO) mice, a genetic model with relevance to ASD and PMDS, have deficits in social recognition in adulthood, but the developmental mechanisms underlying this dysfunction remain unknown. We found that Shank3B KOs have deficits in short-term social recognition during development that persist into adulthood along with CA2 network aberrations. In CA2, perineuronal nets (PNNs), extracellular matrix structures, support social recognition in adult mice. In developing CA2, we found excessive PNNs in KOs, greater sequestration of the guidance cue semaphorin-3A, and overgrowth of afferents. Reduction of PNN levels restored semaphorin-3A, afferent input to CA2, and social recognition, which persisted into adulthood and partially normalized CA2 network activity. These findings suggest that excess CA2 PNN formation impairs social recognition by disrupting afferent input, effects that are reversible by early life intervention.