Egr2 inhibition of PDGFRα in oligodendrocytes is necessary for resocialization normalizing cooperation defects in early socially isolated mice

Social neglect is a major contributing factor to social behavior impairment during adolescence, thus it is crucial for exploring its underlying mechanism and therapeutic targets. In this study, we found social isolation (SI) mice who resocialized with group housing (GH) mice improved their impairments in social cooperation and myelination in the medial prefrontal cortex (mPFC). However, resocialization between SI mice did not correct the above disorders. The partition model of behavioral interaction negated the behavioral and pathological improvements by resocialization with GH mice. Early growth response 2 (Egr2) is essential for establishment and maintenance of cooperative behavior. In this study, the regulating role of Egr2 was reconfirmed by specifically knockdown and overexpressed Egr2 in mPFC oligodendrocytes (OLs). mPFC RNA-sequencing (RNA-seq) analysis and enzyme-linked immunosorbent assay further showed that the level of serum corticosterone (Cort) was increased by SI. Additionally, we observed that SI mice’s myelination and social cooperation behavior were improved or inhibited when their companions received intraperitoneal injection of metyrapone or Cort during resocialization. RNA-seq analysis of cultured primary OLs combined with resocialization models further revealed that Egr2 participates in myelin formation by inhibiting platelet derived growth factor receptor alpha (PDGFRα). This finding revealed the neurobiological mechanism by which Egr2 participates in the regulation of impaired cooperative behavior in early SI mice through the inhibition of PDGFRα expression in OLs and the involvement of resocialization.