biostudies-literatureChiola SAlan B. Slifka FoundationU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and StrokeWhitehall FoundationNIMH NIH HHSBrain Research FoundationBrain and Behavior Research FoundationNINDS NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Mental Health4670-4686https://www.ebi.ac.uk/biostudies/studies/S-EPMC8349370biostudies-literatureUnknown26(9)Genetic abnormalities in synaptic proteins are common in individuals with autism; however, our understanding of the cellular and molecular mechanisms disrupted by these abnormalities is limited. SHANK3 is a postsynaptic scaffolding protein of excitatory synapses that has been found mutated or deleted in most patients with 22q13 deletion syndrome and about 2% of individuals with idiopathic autism and intellectual disability. Here, we generated CRISPR/Cas9-engineered human pluripotent stem cells (PSCs) with complete hemizygous SHANK3 deletion (SHANK3^+/-), which is the most common genetic abnormality in patients, and investigated the synaptic and morphological properties of SHANK3-deficient PSC-derived cortical neurons engrafted in the mouse prefrontal cortex. We show that human PSMolecular psychiatryDefective AMPA-mediated synaptic transmission and morphology in human neurons with hemizygous SHANK3 deletion engrafted in mouse prefrontal cortex.PMC8349370NS104963-01A1R01 MH113670R21 NS1049631R01MH113670 - 01A1Chiola SLazarenko RMShcheglovitov ANapan KLCui JWang YArmstrong CJfalseDefective AMPA-mediated synaptic transmission and morphology in human neurons with hemizygous SHANK3 deletion engrafted in mouse prefrontal cortex.Genetic abnormalities in synaptic proteins are common in individuals with autism; however, our understanding of the cellular and molecular mechanisms disrupted by these abnormalities is limited. SHANK3 is a postsynaptic scaffolding protein of excitatory synapses that has been found mutated or deleted in most patients with 22q13 deletion syndrome and about 2% of individuals with idiopathic autism and intellectual disability. Here, we generated CRISPR/Cas9-engineered human pluripotent stem cells (PSCs) with complete hemizygous SHANK3 deletion (SHANK3^+/-), which is the most common genetic abnormality in patients, and investigated the synaptic and morphological properties of SHANK3-deficient PSC-derived cortical neurons engrafted in the mouse prefrontal cortex. We show that human PS2021-01-01T00:00:00Z2021 Sep2025-04-19T06:41:26.483Z2022-02-11T13:11:01.801ZS-EPMC83493703355865110.1038/s41380-021-01023-2