In contrast to postmortem human brains, hiPSC-derived model systems are actively developing and express dynamic genetic programs that regulate the process of cell proliferation, differentiation into neural precursors and subsequently into mature neurons and glial cells. These systems consequently enable the study of genetic programs that are active in the prenatal brain, as gene expression changes dramatically at the time of birth23. As noted above, postmortem brain tissue is also often distorted by other disease processes, making it hard to distinguish causes from consequences and experimental artifacts. In principle, hiPSCs can recapitulate the progression of brain development from embryonic day zero to various stages of maturity. One drawback is that hiPSC-derived brain cells are not as complex as those in the brain, and technical reasons currently limit our ability to grow these cells long enough in vitro to recapitulate the perinatal and adult brain. Nevertheless, hiPSC-derived models can allow us to examine and understand how the aberrations in brain structure, composition and connectivity we observe in postmortem and imaging studies develop, and to derive quantifiable measures of neuronal morphology, function, electrophysiology, connectivity, and gene expression from multiple timepoints during embryonic brain development (Figure 1).
