title: Direct Induction and Functional Maturation of Forebrain GABAergic Neurons from Human Pluripotent Stem Cells.
abstract: 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.
authors: Cancer Stem Cell Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Department of Neurology, National Neuroscience Institute, 20 College Road, Singapore 169856, Singapore. Electronic address: alfred_xy_sun@nni.com.sg.
authors: Alfred Xuyang
authors: AX
authors: Sun
authors: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Graduate School for integrative Sciences and Engineering, National University of Singapore, Singapore 117456, Singapore.
authors: Qiang
authors: Q
authors: Yuan
authors: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Graduate School for integrative Sciences and Engineering, National University of Singapore, Singapore 117456, Singapore.
authors: Shawn
authors: S
authors: Tan
authors: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
authors: Yixin
authors: Y
authors: Xiao
authors: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
authors: Danlei
authors: D
authors: Wang
authors: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
authors: Audrey Tze Ting
authors: AT
authors: Khoo
authors: Cancer Stem Cell Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
authors: Levena
authors: L
authors: Sani
authors: Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
authors: Hoang-Dai
authors: HD
authors: Tran
authors: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
authors: Paul
authors: P
authors: Kim
authors: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
authors: Yong Seng
authors: YS
authors: Chiew
authors: Department of Structure and Function of Neural Network, Korea Brain Research Institute, Daegu 701-300, Republic of Korea.
authors: Kea Joo
authors: KJ
authors: Lee
authors: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
authors: Yi-Chun
authors: YC
authors: Yen
authors: Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Graduate School for integrative Sciences and Engineering, National University of Singapore, Singapore 117456, Singapore.
authors: Huck Hui
authors: HH
authors: Ng
authors: Cancer Stem Cell Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
authors: Bing
authors: B
authors: Lim
authors: Molecular Neurophysiology Laboratory, Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. Electronic address: shawn.je@duke-nus.edu.sg.
authors: Hyunsoo Shawn
authors: HS
authors: Je
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D018920:Coculture Techniques; D059330:GABAergic Neurons / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007395:Interneurons / Q000166:cytology / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D061251:Primary Cell Culture; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism*; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid; C065500:ASCL1 protein, human; C000619438:DLX2 protein, human; C121947:LHX6 protein, human
keywords: GABA; direct conversion; human pluripotent stem cells; interneuron; synapse