Multielectrode Arrays for Functional Phenotyping of Neurons from Induced Pluripotent Stem Cell Models of Neurodevelopmental Disorders

SIMPLE SUMMARY: Multielectrode array technology allows researchers to record the spontaneous firing activity of cultured neurons over a period of multiple weeks or months. These data can be valuable for understanding how the functional relationships between neurons evolve as they begin to form connections and wire into a functional network. This technology has been adopted by researchers using stem cells to produce human neurons in culture to study neurodevelopmental disorders. However, the dizzying complexity and scale of the data generated have posed some challenges with the analysis and interpretation of experimental results. Here, we first provide historical context as to why multielectrode array platforms were originally developed, and use this perspective to explore some of the challenges currently facing the field. We then highlight new analysis methods, provide some guidance for improving the analysis of multielectrode array data, and discuss standardizing how these findings are communicated in scientific publications. ABSTRACT: In vitro multielectrode array (MEA) systems are increasingly used as higher-throughput platforms for functional phenotyping studies of neurons in induced pluripotent stem cell (iPSC) disease models. While MEA systems generate large amounts of spatiotemporal activity data from networks of iPSC-derived neurons, the downstream analysis and interpretation of such high-dimensional data often pose a significant challenge to researchers. In this review, we examine how MEA technology is currently deployed in iPSC modeling studies of neurodevelopmental disorders. We first highlight the strengths of in vitro MEA technology by reviewing the history of its development and the original scientific questions MEAs were intended to answer. Methods of generating patient iPSC-derived neurons and astrocytes for MEA co-cultures are summarized. We then discuss challenges associated with MEA data analysis in a disease modeling context, and present novel computational methods used to better interpret network phenotyping data. We end by suggesting best practices for presenting MEA data in research publications, and propose that the creation of a public MEA data repository to enable collaborative data sharing would be of great benefit to the iPSC disease modeling community.