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Defective AMPA-mediated synaptic transmission and morphology in human neurons with hemizygous SHANK3 deletion engrafted in mouse prefrontal cortex

Molecular Psychiatry volume 26, pages 4670–4686 (2021)Cite this article

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Abstract

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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Fig. 1: SHANK3 hemizygosity in human ESC-derived neurons caused synaptic connectivity deficits in vitro.
Fig. 2: Anatomical integration of human neurons transplanted into the mouse PFC.
Fig. 3: AMPAR-mediated excitatory synaptic deficits in developing SHANK3 +/− neurons co-engrafted with iCtrl neurons in the mouse PFC.
Fig. 4: Decreased excitatory synaptic transmission, spines, and dendritic arbors in mature SHANK3 +/− neurons co-engrafted with iCtrl neurons in the mouse PFC.

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Acknowledgements

We thank Ricardo Dolmetsch and Theo Palmer for providing iPSC lines; Yuanyuan Wu for helping with generating homozygous CRISPR/Cas9-engineered stem cells; Travis Philyaw for helping with mapping deletions; Brittney Nhem and Nico Edgar for helping with image analysis; Megan Williams, Edward Callaway, Liqun Luo, and John Naughton for plasmids; Chris Rodesch and the University of Utah Cell Imaging Core for assisting with microscopy, Jay Spampanato and Peter West for advising on intracranial injections and slice physiology; Monica Vetter, Richard Dorsky, and Sungjin Park for commenting on the manuscript. This work was supported by grants from the NIMH, NINDS, Brain Research Foundation, Brain and Behavior Research Foundation, Whitehall Foundation, Alan B. Slifka Foundation, and Utah Neuroscience and Genome Project Initiatives.

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  1. These authors contributed equally: Simone Chiola, Kandy Napan, Yueqi Wang

Authors and Affiliations

  1. Departments of Neurobiology, University of Utah, Salt Lake City, UT, USA

    Simone Chiola, Kandy L. Napan, Yueqi Wang, Celeste J. Armstrong & Aleksandr Shcheglovitov

  2. Neuroscience Graduate Program, University of Utah, Salt Lake City, UT, USA

    Yueqi Wang & Aleksandr Shcheglovitov

  3. Departments of Pharmacology, Vanderbilt University, Nashville, TN, USA

    Roman M. Lazarenko

  4. Department of Cell Biology and Neurosciences, Montana State University, Bozeman, MT, USA

    Jun Cui

  5. Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA

    Aleksandr Shcheglovitov

  6. Department of Adult Psychiatry, University of Utah, Salt Lake City, UT, USA

    Aleksandr Shcheglovitov

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Chiola, S., Napan, K.L., Wang, Y. et al. Defective AMPA-mediated synaptic transmission and morphology in human neurons with hemizygous SHANK3 deletion engrafted in mouse prefrontal cortex. Mol Psychiatry 26, 4670–4686 (2021). https://doi.org/10.1038/s41380-021-01023-2

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