By stimulating or recording electrical activity, microelectrode arrays implanted in the brain have created a renaissance in the treatment of neurological diseases and injuries. Likewise, these devices are an enabling technology to understand normal brain function and behavior. However, questions remain regarding the relationship between the biological response to implanted electrodes, their chronic performance, and features of their design. It is my lab’s goal to understand the basic science underlying the interaction between implanted electrodes and brain cells, and to provide guiding principles to improve device design and performance as a result. Recently, we have found novel effects of implanted silicon and polyimide-based electrode arrays on the structure and function of local neurons, including alterations in ion channel expression, synaptic transporter expression, dendritic spine density, and excitability. Results of quantitative immunohistochemistry demonstrate a progressive local increase in the expression of potassium ion channels and inhibitory transporters surrounding devices implanted in the brains of rats over time, indicating a potential shift toward hypoexcitability over the 6-week time course studied. Two-photon laser scanning microscopy in brain slice preparations revealed significant local spine loss surrounding implants, coupled with observations of changes in the frequency of excitatory post-synaptic currents. More recently, RNA-sequencing has complemented our understanding of these observed plasticity effects, where a current goal is to characterize the molecular identity and function of neurons and non-neurons surrounding implanted electrodes. Our results suggest a novel role of local plasticity surrounding devices in chronic signal loss and instability, and we are currently working to assess and perturb local gene expression to reveal potential underlying mechanisms.