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Epigenetic silencing of FMR1 results in loss of the Fragile X Mental Retardation Protein (FMRP). Although most studies to date have focused on excitatory neurons, recent evidence suggests that GABAergic inhibitory networks are also affected. To investigate human GABAergic neurogenesis, we established a method to reproducibly derive inhibitory neurons from multiple FXS and control human pluripotent stem cell (hPSC) lines. Electrophysiological analyses suggested that the developing FXS neurons had a delay in the GABA functional switch, a transition in fetal development that converts the GABAA channel\u2019s function from depolarization to hyperpolarization, with profound effects on the developing brain. To investigate the cause of this delay, we analyzed 14 400 single-cell transcriptomes from FXS and control cells at 2 stages of GABAergic neurogenesis. While control and FXS cells were similar at the earlier time point, the later-stage FXS cells retained expression of neuroblast proliferation-associated genes and had lower levels of genes associated with action potential regulation, synapses, and mitochondria compared with controls. Our analysis suggests that loss of FMRP prolongs the proliferative stage of progenitors, which may result in more neurons remaining immature during the later stages of neurogenesis. This could have profound implications for homeostatic excitatory-inhibitory circuit development in FXS, and suggests a novel direction for understanding disease mechanisms that may help to guide therapeutic interventions.<\/jats:p>","DOI":"10.1093\/stcltm\/szac022","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T11:12:37Z","timestamp":1649934757000},"page":"613-629","source":"Crossref","is-referenced-by-count":22,"title":["Maturation Delay of Human GABAergic Neurogenesis in Fragile X Syndrome Pluripotent Stem Cells"],"prefix":"10.1093","volume":"11","author":[{"given":"Ai","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Scripps Research , La Jolla, CA , USA"},{"name":"Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research , La Jolla, CA , USA"},{"name":"Aspen Neuroscience, Inc. 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A","family":"Pouladi","sequence":"additional","affiliation":[{"name":"Department of Physiology, National University of Singapore , Singapore"},{"name":"Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research (A*STAR) , Singapore"},{"name":"British Columbia Children\u2019s Hospital Research Institute, Department of Medical Genetics, University of British Columbia , Vancouver , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Sanna","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, Scripps Research , La Jolla, CA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Boland","sequence":"additional","affiliation":[{"name":"Institute for Genomic Medicine, Columbia University Irving Medical Center , New York, NY , USA"},{"name":"Department of Neurology, Columbia University , New York, NY , 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