Cellular neuroscience

Excitatory postsynaptic potential

Transcriptome

Neuroscience

Receptor

Autism

Mathematics

Dendrite (mathematics)

Biology

Gene

Induced pluripotent stem cell

Synapse

Embryonic stem cell

Gene expression

Developmental psychology

Inhibitory postsynaptic potential

Psychology

Postsynaptic potential

Geometry

Autism spectrum disorder

Genetics

Nature Neuroscience

Heterozygous loss-of-function mutations in SHANK2 are associated with autism spectrum disorder (ASD). We generated cortical neurons from induced pluripotent stem cells derived from neurotypic and ASD-affected donors. 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 observed increases in dendrite length, dendrite complexity, synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 mutation. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. 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. Our findings provide evidence for hyperconnectivity and altered transcriptome in SHANK2 neurons derived from ASD subjects. Using a novel assay, Ellis et al. show that stem cell-derived neurons from individuals with autism carrying SHANK2 mutations are hyperconnected, have impaired activity-dependent dendrite extension, and have perturbed transcription of ASD gene modules.

SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons