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Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16622-7. doi: 10.1073/pnas.1316240110. Epub 2013 Sep 17.

Neurons generated by direct conversion of fibroblasts reproduce synaptic phenotype caused by autism-associated neuroligin-3 mutation.

Author information

1
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.

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.

KEYWORDS:

cellular reprogramming; neurexin; postsynaptic density; stem cells; synapse

PMID:
24046374
PMCID:
PMC3799342
DOI:
10.1073/pnas.1316240110
[Indexed for MEDLINE]
Free PMC Article
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