Intracortical electrodes for brain–machine interfaces rely on intimate contact with tissues for recording signals and stimulating neurons. However, the long-term viability of intracortical electrodes in vivo is poor, with a major contributing factor being the development of a glial scar. In vivo approaches for evaluating responses to intracortical devices are resource intensive and complex, making statistically significant, high throughput data difficult to obtain. In vitro models provide an alternative to in vivo studies; however, existing approaches have limitations which restrict the translation of the cellular reactions to the implant scenario. Notably, there is no current robust model that includes astrocytes, microglia, oligodendrocytes and neurons, the four principle cell types, critical to the health, function and wound responses of the central nervous system (CNS). In previous research a co-culture of primary mouse mature mixed glial cells and immature neural precursor cells were shown to mimic several key properties of the CNS response to implanted electrode materials. However, the method was not robust and took up to 63 days, significantly affecting reproducibility and widespread use for assessing brain-material interactions. In the current research a new co-culture approach has been developed and evaluated using immunocytochemistry and quantitative polymerase chain reaction (qPCR). The resulting method reduced the time in culture significantly and the culture model was shown to have a genetic signature similar to that of healthy adult mouse brain. This new robust CNS culture model has the potential to significantly improve the capacity to translate in vitro data to the in vivo responses.