Programmed cell death (PCD) is essential for regulating cell homeostasis in the developing brain. Cell populations that undergo massive PCD in the cortex include the first wave of oligodendrocyte precursor cells (firstOPCs) and most of GABAergic interneurons, which die postnatally within the same period. Furthermore, firstOPCs and most interneurons share common embryonic origins. Here we investigated how PCD of both firstOPCs and their lineage-related interneurons impact behavior and cortical networks. We used behavioral assays, patch-clamp recordings and immunostainings in two mouse models in which the pro-apoptotic factor BAX was genetically inactivated: Int-oligo:BAX which targets lineage-related interneurons and firstOPCs and Oligo:BAX which targets OPCs only. Both lines performed as well as their controls in behavioral tests related with locomotor activity, anxiety and object recognition memory. We also assessed spatial memory and cognitive flexibility, using a Barnes maze test over two weeks. In the first week, neither of the two lines showed hippocampal-dependent spatial learning and memory impairments. However, in the second week, both mutants failed to remember the new escape position during the memory test, and Oligo:BAX mice did not even learn during the learning phase, showing a prefrontal-dependent cognitive flexibility impairment. Patch-clamp recordings in the medial prefrontal cortex revealed an excitation-inhibition (E/I) imbalance in Int-oligo:BAX mice but not in Oligo:BAX mice, suggesting that an early defect in the regulation of the oligodendroglia is sufficient to induce severe cognitive deficits without altering the E/I ratio. Our results highlight the importance of oligodendroglial homeostasis in brain function.