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 improved by targeted intervention in adulthood.Significance Statement Early-life adversity (ELA) alters social behavior and increases the likelihood of developing neuropsychiatric disease in humans. Using a mouse model, we found that social memory in males is negatively affected by ELA in males but not females. This deficit is accompanied by increased intensity of perineuronal nets, extracellular matrix structures that regulate plasticity, in the CA2 region of the hippocampus in ELA males. Lowering PNNs in the adult ELA male CA2 restores social memory suggesting that intervention in adulthood effectively corrects social dysfunction that arises during development.