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Gamma-aminobutyric acid (GABA)-releasing interneurons play an important modulatory role in the cortex and have been implicated in multiple neurological disorders. Patient-derived interneurons could provide a foundation for studying the pathogenesis of these diseases as well as for identifying potential therapeutic targets. Here, we identified a set of genetic factors that could robustly induce human pluripotent stem cells (hPSCs) into GABAergic neurons (iGNs) with high efficiency. We demonstrated that the human iGNs express neurochemical markers and exhibit mature electrophysiological properties within 6–8 weeks. Furthermore, in vitro, iGNs could form functional synapses with other iGNs or with human-induced glutamatergic neurons (iENs). Upon transplantation into immunodeficient mice, human iGNs underwent synaptic maturation and integration into host neural circuits. Taken together, our rapid and highly efficient single-step protocol to generate iGNs may be useful to both mechanistic and translational studies of human interneurons.
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•We identify factors that directly induce GABAergic neurons (iGNs) from hPSCs•iGNs express telencephalic interneuron markers and the subtype marker SST•iGNs functionally mature, release GABA, and generate synaptic networks in vitro•iGNs integrate into host synaptic circuits in vivo
Sun et al. identify a combination of genetic factors that can directly transform hPSCs into forebrain GABAergic neurons with high efficiency. These induced neurons express canonical interneuron markers and exhibit mature functional properties, suggesting that they may be useful for neuronal subtype-specific studies and cortical network assembly.