Regrouping reverses social impairments and prefrontal parvalbumin-perineuronal nets alterations induced by post-weaning social isolation in male mice

Social isolation during early development can lead to abnormal adult behavior. These behavioral deficits are often associated with disruptions of perineuronal nets (PNNs), a condensed form of the brain's extracellular matrix. PNNs regulate neuroplasticity by enwrapping parvalbumin-expressing (PV) interneurons, and abnormal maturation of PNN in early life has been associated with behavioral deficits reminiscent of those following isolation. Past studies demonstrate that social regrouping following early isolation can improve behavioral deficits, but the underlying mechanisms of this recovery are unknown. This study aims to establish the effects of regrouping on PNNs as a potential cellular mediator of the behavioral rescue. We hypothesize that regrouping mice during adolescence will rescue early isolation-induced behavioral deficits associated with PNN restoration. We assigned male mice to group-housed, isolated, or isolated/regrouped conditions from weaning age until end of adolescence (postnatal day 21 to 67; N = 8-10/group). Behaviors were assessed in the open field, novel object recognition, Y-maze, and social interaction tests. Number of PV cells and PNNs were quantified in the prefrontal cortex (PFC), dorsal and ventral hippocampus. Our results showed that early isolation led to hypersociability, which was rescued by regrouping; however regrouping also increased anxiety. Furthermore, isolation reduced the propotion of PV cells surrounded by PNNs in the PFC, and regrouping reversed this effect and increased the total PNN count in PFC while it decreased PV/PNN count in the ventral hippocampus. These findings suggest that behavioral improvements in the social domain may be associated with region-specific changes in PV interneuron plasticity.