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The mammalian brain is a very complex organ containing an estimated 200 billion cells in humans. Therefore, studying human brain development has become very challenging given all the data that are available from different approaches, notably genetic studies. Recent pluripotent stem cell methods have given rise to the possibility of modeling neurodevelopmental diseases associated with genetic defects. Fibroblasts from patients have been reprogrammed into pluripotent stem cells to derive appropriate neuronal lineages. They specifically include different subtypes of cortical neurons that are at the core of human-specific cognitive abilities. The use of neurons derived from induced pluripotent stem cells (iPSC) has led to deciphering convergent and pleiotropic neuronal synaptic phenotypes found in neurodevelopmental disorders such as autism spectrum disorders (ASD) and their associated syndromes. In addition to these initial studies, remarkable progress has been made in the field of stem cells, with the major objective of reproducing the in vivo maturation steps of human neurons. Recently, several studies have demonstrated the ability of human progenitors to respond to guidance cues and signals in vivo that can direct neurons to their appropriate sites of differentiation where they become fully mature neurons. We provide a brief overview on research using human iPSC in ASD and associated syndromes and on the current understanding of new theories using the re-implantation of neural precursors in mouse brain.

Using human induced pluripotent stem cells (iPSC), recent studies have shown that the events underlying autism spectrum disorders (ASD) can occur during neonatal development. We previously analyzed the iPSC-derived pyramidal cortical neurons of a subset of patients with ASD carrying de novo heterozygous mutations in postsynaptic SHANK3 protein, in culture. We reported altered spinogenesis of those neurons. The transplantation of human iPSC-derived neuronal precursors into mouse brain represents a novel option for in vivo analysis of mutations affecting the human brain. In this study, we transplanted the neuronal precursor cells (NPC) into the cortex of newborn mice to analyze their integration and maturation at early stages of development and studied axonal projections of transplanted human neurons into adult mouse brain. We then co-transplanted NPC from a control individual and from a patient carrying a de novo heterozygous SHANK3 mutation. We observed a reduction in cell soma size of selective neuronal categories and in axonal projections at 30 days post-transplantation. In contrast to previous in vitro studies, we did not observe any alteration in spinogenesis at this early age. The humanized chimeric mouse models offer the means to analyze ASD-associated mutations further and provide the opportunity to visualize phenotypes in vivo.

The synaptic protein SHANK3 encodes a multidomain scafold protein expressed at the postsynapticdensity of neuronal excitatory synapses. We previously identifed de novo SHANK3 mutations inpatients with autism spectrum disorders (ASD) and showed that SHANK3 represents one of the majorgenes for ASD. Here, we analyzed the pyramidal cortical neurons derived from induced pluripotent stemcells from four patients with ASD carrying SHANK3 de novo truncating mutations. At 40–45 days afterthe diferentiation of neural stem cells, dendritic spines from pyramidal neurons presented variablemorphologies: flopodia, thin, stubby and muschroom, as measured in 3D using GFP labeling andimmunofuorescence. As compared to three controls, we observed a signifcant decrease in SHANK3mRNA levels (less than 50% of controls) in correlation with a signifcant reduction in dendritic spinedensities and whole spine and spine head volumes. These results, obtained through the analysis of denovo SHANK3 mutations in the patients’ genomic background, provide further support for the presenceof synaptic abnormalities in a subset of patients with ASD.