Journal
MOLECULAR PSYCHIATRY
Volume 26, Issue 9, Pages 4670-4686Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-021-01023-2
Keywords
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Funding
- NIMH
- NINDS
- Brain Research Foundation
- Brain and Behavior Research Foundation
- Whitehall Foundation
- Alan B. Slifka Foundation
- Utah Neuroscience Initiative
- Utah Genome Project Initiative
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The study utilized CRISPR/Cas9-engineered human pluripotent stem cells with SHANK3 deletion to investigate synaptic and morphological properties in the mouse prefrontal cortex. Findings showed that SHANK3-deficient human neurons have reduced synaptic transmission and impaired dendritic arbors and spines, providing a new platform for studying connectivity deficits in genetic neurodevelopmental disorders associated with autism.
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 PSC-derived neurons integrate into the mouse cortex by acquiring appropriate cortical layer identities and by receiving and sending anatomical projections from/to multiple different brain regions. We also demonstrate that SHANK3-deficient human neurons have reduced AMPA-, but not NMDA- or GABA-mediated synaptic transmission and exhibit impaired dendritic arbors and spines, as compared to isogenic control neurons co-engrafted in the same brain region. Together, this study reveals specific synaptic and morphological deficits caused by SHANK3 hemizygosity in human cortical neurons at different developmental stages under physiological conditions and validates the use of co-engrafted control and mutant human neurons as a new platform for studying connectivity deficits in genetic neurodevelopmental disorders associated with autism.
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