Development of a platform to investigate long term potentiation in human iPSC-derived neuronal networks

Although impairment of long-term potentiation (LTP) is a common feature of many neurological disorders, studies in humans are limited by inaccessibility of the brain. Human induced pluripotent stem cells (hiPSC) provide a unique opportunity to study LTP, especially in disease specific genetic backgrounds. We describe a multi-electrode array (MEA)-based assay to investigate chemically induced LTP (cLTP) in networks of hiPSC-derived midbrain dopaminergic (DA) and cortical neuronal populations. We demonstrate potentiation of activity that lasts for days, allowing for studies of the late phases of LTP. We show that cLTP on midbrain DA neuronal networks is largely independent of the N-methyl-D-aspartate receptor (NMDAR), and demonstrate partial dependence on brain derived neurotrophic factor (BDNF), as well as other factors released into the medium. Finally, we describe activity-regulated gene expression induced by cLTP. In summary, this cLTP-MEA assay platform will enable phenotype discovery and higher throughput analyses of synaptic plasticity on hiPSC-derived neurons. Study of activity regulated gene expression induced by chemical long term potentiation (cLTP), mediated by forskolin and rolipram (FSK/ROL) treatment, on human induced pluripotent stem cell (hiPSC) derived midbrain dopaminargic neuronal cell population co-cultured with hIPSC derived astrocytes, five hours post washout of FSK/ROL.