Post-weaning social isolation in male mice leads to abnormal aggression and disrupted network organization in the prefrontal cortex: Contribution of parvalbumin interneurons with or without perineuronal nets

Adverse social experiences during childhood increase the risk of developing aggression-related psychopathol- ogies. The prefrontal cortex (PFC) is a key regulator of social behavior, where experience-dependent network development is tied to the maturation of parvalbumin-positive (PV+) interneurons. Maltreatment in childhood could impact PFC development and lead to disturbances in social behavior during later life. However, our knowledge regarding the impact of early-life social stress on PFC operation and PV+ cell function is still scarce. Here, we used post-weaning social isolation (PWSI) to model early-life social neglect in mice and to study the associated neuronal changes in the PFC, additionally distinguishing between the two main subpopulations of PV+ interneurons, i.e. those without or those enwrapped by perineuronal nets (PNN). For the first time to such detailed extent in mice, we show that PWSI induced disturbances in social behavior, including abnormal aggression, excessive vigilance and fragmented behavioral organization. PWSI mice showed altered resting-state and fighting-induced co-activation patterns between orbitofrontal and medial PFC (mPFC) subregions, with a particularly highly elevated activity in the mPFC. Surprisingly, aggressive interaction was associated with a higher recruitment of mPFC PV+ neurons that were surrounded by PNN in PWSI mice that seemed to mediate the emergence of social deficits. PWSI did not affect the number of PV+ neurons and PNN density, but enhanced PV and PNN intensity as well as cortical and subcortical glutamatergic drive onto mPFC PV+ neurons. Our results suggest that the increased excitatory input of PV+ cells could emerge as a compensatory mechanism for the PV+ neuron-mediated impaired inhibition of mPFC layer 5 pyramidal neurons, since we found lower numbers of GABAergic PV+ puncta on the perisomatic region of these cells. In conclusion, PWSI leads to altered PV-PNN activity and impaired excitatory/inhibitory balance in the mPFC, which possibly contributes to social behav- ioral disruptions seen in PWSI mice. Our data advances our understanding on how early-life social stress can impact the maturing PFC and lead to the development of social abnormalities in adulthood.