title: Neurons generated by direct conversion of fibroblasts reproduce synaptic phenotype caused by autism-associated neuroligin-3 mutation.
abstract: Recent studies suggest that induced neuronal (iN) cells that are directly transdifferentiated from nonneuronal cells provide a powerful opportunity to examine neuropsychiatric diseases. However, the validity of using this approach to examine disease-specific changes has not been demonstrated. Here, we analyze the phenotypes of iN cells that were derived from murine embryonic fibroblasts cultured from littermate wild-type and mutant mice carrying the autism-associated R704C substitution in neuroligin-3. We show that neuroligin-3 R704C-mutant iN cells exhibit a large and selective decrease in AMPA-type glutamate receptor-mediated synaptic transmission without changes in NMDA-type glutamate receptor- or in GABAA receptor-mediated synaptic transmission. Thus, the synaptic phenotype observed in R704C-mutant iN cells replicates the previously observed phenotype of R704C-mutant neurons. Our data show that the effect of the R704C mutation is applicable even to neurons transdifferentiated from fibroblasts and constitute a proof-of-concept demonstration that iN cells can be used for cellular disease modeling.
authors.affiliation: Departments of Molecular and Cellular Physiology and Pathology, Howard Hughes Medical Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Soham
authors.initials: S
authors.lastname: Chanda
authors.forename: Samuele
authors.initials: S
authors.lastname: Marro
authors.forename: Marius
authors.initials: M
authors.lastname: Wernig
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000503:physiopathology*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D054338:Cell Transdifferentiation / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D018091:Receptors, AMPA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; C098004:neuroligin 3
keywords: cellular reprogramming; neurexin; postsynaptic density; stem cells; synapse
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