Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations
Résumé
The synaptic protein SHANK3 encodes a multidomain scafold protein expressed at the postsynaptic
density of neuronal excitatory synapses. We previously identifed 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 diferentiation of neural stem cells, dendritic spines from pyramidal neurons presented variable
morphologies: flopodia, thin, stubby and muschroom, as measured in 3D using GFP labeling and
immunofuorescence. As compared to three controls, we observed a signifcant decrease in SHANK3
mRNA levels (less than 50% of controls) in correlation with a signifcant 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.
Domaines
Sciences du Vivant [q-bio]Origine | Accord explicite pour ce dépôt |
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