In this study we have investigated the plasticity-related changes observed in the medial prefrontal cortex (mPFC) of a dual-hit model of schizophrenia developed in rats. The dual-hit model combines an injection of non-competitive NMDA receptor antagonist MK-801 at P7 and 8 weeks of postweaning social isolation. The model was developed in both male and female rats. At P90 RNA sequencing (RNAseq) was conducted on the prefrontal cortex. Differential expressed genes (DEGs) and enriched categories were validated in silico via MAGMA using GWAS summary statistics of the Psychiatric Genomics Consortium of schizophrenia (67,390 cases and 94,015 controls). Histological studies were conducted at P90 on coronal sections of brain tissue, examining the infralimbic (IL) and prelimbic regions (PL), and targeting neurons expressing OTX2, parvalbumin (PV) and perineuronal nets (PNN). RNA-seq of the prefrontal cortex indicates that, in males, observed alterations are predominantly linked to immune system processes. Conversely, in females, the identified changes are more prominently associated with cerebral functions. Histological results revealed alterations in plasticity markers, with changes in PL exhibiting greater significance. The ‘dual hit’ rat model of schizophrenia, as evidenced by recapitulated symptoms, offers valuable insights into the pathophysiology of the disorder. RNA-seq results underscore the relevance of immune and synaptic functions, with concurrent evidence of altered plasticity in both histological and RNA-seq analyses. These findings contribute to a comprehensive understanding of sex-specific molecular alterations, providing a foundation for further exploration in schizophrenia.