The advent of technology for inducing defined neuronal subtypes from human cells has provided an important step toward understanding and modeling neuropsychiatric diseases. Progress in this understanding is still greatly limited and heavily based on non-primate animal models or mixed two-dimensional human neuronal cultures lacking defined connectivity. Animal models have provided clues regarding possible circuitry and mechanisms involved in human disease; however, they have not delivered a high level of successful translation of scientific findings into new therapeutics. To bridge this gap, better modeling systems are greatly needed. We have developed a high-throughput compartmentalized system for human neurocircuitry studies, which builds upon previous approaches using microchannels to segregate cell bodies and enable axons to relay cell to cell communication between chambers.2–4,7,8,11 Our device has two compartments built into each well within a 96 well plate to allow HTS of therapeutic candidates within a well-defined, simplified neurocircuitry. Neurons seeded into the device remain in distinct compartments up to 7 weeks in culture after plating (Fig. 3) and could enable morphological analysis of cultures (Fig. 4). Importantly, these neurons establish functional synaptic contacts and coordinated network activity between compartments (Fig. 5–7).
