![]() NMDA receptor-dependent glutamate excitotoxicity in human embryonic stem cell-derived neurons. Functional neural development from human embryonic stem cells: accelerated synaptic activity via astrocyte coculture. MECP2 is post-transcriptionally regulated during human neurodevelopment by combinatorial action of RNA-binding proteins and miRNAs. Complete disruption of autism-susceptibility genes by gene editing predominantly reduces functional connectivity of isogenic human neurons. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Opportunities and challenges of pluripotent stem cell neurodegenerative disease models. Creating patient-specific neural cells for the in vitro study of brain disorders. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Human neuropsychiatric disease modeling using conditional deletion reveals synaptic transmission defects caused by heterozygous mutations in NRXN1. MECP2e1 isoform mutation affects the form and function of neurons derived from Rett syndrome patient iPS cells. Our findings provide evidence for hyperconnectivity and altered transcriptome in SHANK2 neurons derived from ASD subjects.ĭjuric, U. The transcriptome in isogenic SHANK2 neurons was perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 mutation. We observed increases in dendrite length, dendrite complexity, synapse number, and frequency of spontaneous excitatory postsynaptic currents. We developed sparse coculture for connectivity assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We generated cortical neurons from induced pluripotent stem cells derived from neurotypic and ASD-affected donors. Heterozygous loss-of-function mutations in SHANK2 are associated with autism spectrum disorder (ASD).
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