title: Modeling hippocampal neurogenesis using human pluripotent stem cells.
abstract: The availability of human pluripotent stem cells (hPSCs) offers the opportunity to generate lineage-specific cells to investigate mechanisms of human diseases specific to brain regions. Here, we report a differentiation paradigm for hPSCs that enriches for hippocampal dentate gyrus (DG) granule neurons. This differentiation paradigm recapitulates the expression patterns of key developmental genes during hippocampal neurogenesis, exhibits characteristics of neuronal network maturation, and produces PROX1+ neurons that functionally integrate into the DG. Because hippocampal neurogenesis has been implicated in schizophrenia (SCZD), we applied our protocol to SCZD patient-derived human induced pluripotent stem cells (hiPSCs). We found deficits in the generation of DG granule neurons from SCZD hiPSC-derived hippocampal NPCs with lowered levels of NEUROD1, PROX1, and TBR1, reduced neuronal activity, and reduced levels of spontaneous neurotransmitter release. Our approach offers important insights into the neurodevelopmental aspects of SCZD and may be a promising tool for drug screening and personalized medicine.
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Diana Xuan
authors.initials: DX
authors.lastname: Yu
authors.affiliation: Neuroscience Discovery, Novartis Pharma AG, Novartis Institute for Biomedical Research, Postfach, Basel CH-4002, Switzerland.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Di Giorgio
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Maria Carolina
authors.initials: MC
authors.lastname: Marchetto
authors.affiliation: Department of Neuroscience/Psychiatry, Mount Sinai School of Medicine, 1425 Madison Ave, New York, NY 10059, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Brennand
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wright
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Arianna
authors.initials: A
authors.lastname: Mei
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: McHenry
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lisuk
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jaeson Michael
authors.initials: JM
authors.lastname: Grasmick
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Silberman
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Silberman
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Jappelli
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
mesh_terms: D000200:Action Potentials; D002454:Cell Differentiation; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism; D055724:Electrophysiological Phenomena; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D009415:Nerve Net; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000096:biosynthesis; D039904:Pluripotent Stem Cells / Q000166:cytology*; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D018377:Neurotransmitter Agents; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein