Recent studies have revealed an unexpected contribution of oligodendroglial cells to inhibitory circuit establishment and function. Yet, the entire spectrum of oligodendroglia-interneuron interactions as well as the impact of oligodendroglia loss or dysfunction on the development of the inhibitory system are still open issues.Here, we exploited two mouse models where the germinal or the oligodendroglia-specific deletion of citron kinase (i.e. Cit-k KO or Sox10Cre::Cit-k fl/fl mice) leads to the selective ablation of cortical oligodendrocyte progenitor cells (OPCs) during the first two weeks of life. Cit-k KO mice display defective inhibition onto cortical pyramidal neurons and a reduced lifespan due to lethal seizures. Although not showing a spontaneous epileptic phenotype, Sox10Cre::Cit-k fl/fl mice are more vulnerable to epileptogenic drugs compared to their wild-type littermates, indicating that OPC loss was associated with an altered excitation/inhibition balance in both models.In Cit-k KO mice, the pharmacological rescue of cortical OPCs – although not restoring myelination - resulted in a reduced epileptic phenotype and in a significant rescue of the cortical inhibitory neurotransmission. This positive outcome was particularly enhanced when OPC repopulation was achieved by wild-type OPC transplantation, leading to the abrogation of susceptibility to epileptogenic drugs and to a remarkable lengthening of mouse lifespan. Mechanistically, OPC rescue/graft were associated with a strong upregulation of markers indicative of interneuron maturation.Overall, our data indicate that, at neonatal stages, the loss of OPCs is associated with alterations of the cortical inhibitory system which can be rescued by oligodendroglia restoration.