Linking epigenetics to electrophysiology using high-throughput microelectrode array-based hardware with simultaneous optogenetic activation

SUMMARY Post-mitotic neurons in the mammalian brain form synapses that dynamically remodel throughout an individual's lifetime to encode learning and memory. Synaptic plasticity requires spatiotemporal fine-tuning of gene expression in response to neural activity, including rapid transcription of immediate early genes on the time scale of minutes and longer-term chromatin remodeling to promote transcription of secondary response genes on the time scale of hours. In human systems, it is not possible to simultaneously measure epigenetic features and electrophysiology from the same batch of neurons. However, now with the emergence of reproducible protocols for human induced pluripotent stem cell (iPSC)-derived neurons and iPSC-derived human brain organoids, it is possible to do epigenetic studies on the human brain in vitro. At the current time, the gold-standard for measuring electrophysiological properties in human cultured neurons and organoids is the microelectrode array (MEA) technology coupled with hardware for simultaneous optogenetic activation of neural circuits, however no such system is readily available in the Department of Genetics at the University of Pennsylvania. There is a large group of investigators working on neuroepigenetics at UPenn, and access to the MEA system will empower the labs to achieve their overarching goal to conduct human studies linking epigenetic features to neuronal functional electrophysiological properties that are traditionally difficult to measure. Over the long-term, the ability to link neural circuit firing and function to epigenetic signatures will shed light on how genetic and epigenetic defects can cause functional defects in key neural circuit defects in human neurodevelopmental and neurodegenerative disease.