Rathaur, A. B. | Search bioRxiv

bioRxiv2026

Developmental scarcity induces sex differences in social recognition and CA2 perineuronal nets

Early-life adversity has a lasting negative impact on social behavior in both humans and rodents. Sex differences exist in functional outcomes of postnatal stress, but underlying mechanisms remain incompletely explored. Using the limited bedding and nesting paradigm, a mouse model of developmental scarcity, we found sex differences in social behavior with adult males showing impaired social recognition and adult females showing intact social recognition with enhanced social novelty preference. Perineuronal nets, specialized extracellular matrix structures, are known to inhibit developmental plasticity and are concentrated in the CA2 region of the hippocampus in adulthood. We found higher intensity of CA2 perineuronal nets in adult males, but not adult females, after early life adversity. Focal degradation of the extracellular matrix in the CA2 region restored social recognition function in adult males previously subjected to early stress, suggesting that the effects of developmental adversity may be overcome by targeted intervention in adulthood.

neuroscience↗

bioRxiv2025

Developmental CA2 perineuronal net reduction restores social memory in Shank3B KO mice

Individuals with Autism Spectrum Disorder (ASD) and related neurodevelopmental conditions, like Phelan-McDermid syndrome (PMDS), exhibit social recognition deficits. Previous reports using Shank3B knockout (KO) mice, a genetic model with relevance to ASD and PMDS, revealed deficits in social memory in adulthood, but the postnatal onset and mechanisms underlying this dysfunction remain unknown. In the hippocampus, area CA2 contributes to the emergence of social memory during development and remains important for this ability through the lifespan. Perineuronal nets (PNNs), extracellular matrix structures, support social memory in CA2 and help orchestrate critical periods of plasticity in other brain regions. We found that Shank3B KO pups exhibit specific deficits in short-term social recognition and social novelty preference, which become evident at the end of the second postnatal week and persist into adulthood along with CA2 network aberrations. Excessive PNNs in area CA2 were detected in KO pups at the postnatal time when social recognition function typically emerges in healthy pups. This time was also characterized by greater sequestration of the guidance cue semaphorin-3A (sema3A) and overgrowth of afferents from the supramammillary nucleus (SuM) in KOs, suggesting that inordinate PNNs during a sensitive period may disorganize developing CA2 circuitry. Reduction of CA2 PNN levels prior to the onset of social dysfunction recovered social recognition function during development, as well as reduced sema3A and SuM inputs to the CA2. The restoration of behavioral function persisted into adulthood along with partial normalization of CA2 network activity. Together, these findings reveal how excess PNN formation in the developing hippocampus may give rise to impaired social memory by disrupting afferent input, effects that are reversible by early life intervention.

neuroscience↗