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Sci Rep. 2019 Jan 14;9(1):94. doi: 10.1038/s41598-018-36993-x.

Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations.

Author information

1
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.
2
CNRS UMR 3571 « Genes, Synapses and Cognition », Institut Pasteur, Paris, France.
3
Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France.
4
Imagopole, Citech, Institut Pasteur, Paris, France.
5
MaIAGE, INRA, Université Paris-Saclay, 78350, Jouy-en-Josas, France.
6
Bioinformatics and Biostatistics Hub, C3BI, USR 3756 IP CNRS, Institut Pasteur, Paris, France.
7
CECS, I-STEM, AFM, 91030, Evry Cedex, France.
8
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, F-91057, Evry, France.
9
Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Department of Child and Adolescent Psychiatry, Paris, France.
10
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France. isabelle.cloez-tayarani@pasteur.fr.
11
CNRS UMR 3571 « Genes, Synapses and Cognition », Institut Pasteur, Paris, France. isabelle.cloez-tayarani@pasteur.fr.
12
Université Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France. isabelle.cloez-tayarani@pasteur.fr.

Abstract

The synaptic protein SHANK3 encodes a multidomain scaffold protein expressed at the postsynaptic density of neuronal excitatory synapses. We previously identified de novo SHANK3 mutations in patients with autism spectrum disorders (ASD) and showed that SHANK3 represents one of the major genes for ASD. Here, we analyzed the pyramidal cortical neurons derived from induced pluripotent stem cells from four patients with ASD carrying SHANK3 de novo truncating mutations. At 40-45 days after the differentiation of neural stem cells, dendritic spines from pyramidal neurons presented variable morphologies: filopodia, thin, stubby and muschroom, as measured in 3D using GFP labeling and immunofluorescence. As compared to three controls, we observed a significant decrease in SHANK3 mRNA levels (less than 50% of controls) in correlation with a significant reduction in dendritic spine densities and whole spine and spine head volumes. These results, obtained through the analysis of de novo SHANK3 mutations in the patients' genomic background, provide further support for the presence of synaptic abnormalities in a subset of patients with ASD.

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