We have demonstrated the development and application of a novel HTS platform for the investigation of human neuronal circuitry function with defined connectivity patterns in vitro. We have shown that defined neuronal subtypes can form functional synaptic connections and actively communicating neural networks, and that manipulation of neuronal activity in upstream neurons can be functionally correlated with the activity of downstream neurons receiving synaptic inputs. This synaptic relay of information and coordination of neural circuit activity can be pharmacologically modulated and has been validated with the use of human neurons derived from stem cells in our high-throughput platform. Thus, this device is well suited for drug screening applications. Future work extending this approach would involve the use of neurons derived from individuals with different genetic backgrounds and their perturbation with pharmacologic agents aimed to target disease-relevant mechanisms in order to provide testing of “personalized” drug therapies and drug efficacy improvements. Thus, future work using this platform will capitalize on the combined benefits of novel human stem cell technology and microfluidic device engineering to facilitate enhanced drug screening by placing cells within the appropriate circuit context and retaining the high-throughput capacity needed for pharmacological discovery.
