Non-synaptic function of Syngap1 in human neurodevelopmental disorders

SUMMARY Advances in human genomics have dramatically accelerated our understanding of the genetics of complex brain disorders, including autism spectrum disorders (ASD), schizophrenia (SCZ), and intellectual disability (ID). De novo mutations in SYNGAP1 have been reported in ASD, SCZ, and ID, indicating a role for SYNGAP1 in complex brain disorders. These mutations occur throughout the SYNGAP1 gene, which encodes multiple isoforms, and likely affect different SYNGAP1 functions. Most studies of SYNGAP1 have been performed in rodent models within the context of mature synapses and its role at early stages of brain development is largely unknown, especially in humans. Human brain organoids from pluripotent stem cells (PSCs) are emerging as a tractable model to reveal genotype-phenotype correlations in a human cellular context. By leveraging cultures of cortical organoids, we found for the first time the protein expression of SYNGAP1 in human radial glia progenitors (hRGP). Mechanistically, we found that the SYNGAP1’s RASGAP domain is essential for cytoskeletal remodeling of subcellular and intercellular components of hRGP. In addition, we discovered that SYNGAP1 regulates the division mode of hRGP with haploinsufficient organoids exhibiting accelerated cortical neurogenesis. We similarly observed an increased ratio of neurons to radial glial progenitors in an embryonic mouse model of Syngap1 mutation, suggesting that Syngap1 controls the timing of cortical neurogenesis in vitro, in vivo, and across species. Furthermore, we identified SYNGAP1 protein interactors with enriched neurodevelopmental (NDD) risk factors in hRGP. These findings lead to our proposal to determine i) the downstream effectors of Syngap1 in hRGP; ii) the function of the SYNGAP1’s PDZ-ligand domain in controlling cytoskeleton remodeling in hRGP; iii) the impact of SYNGAP1 mutations on the trajectory of distinct human cortical cell types; and iv) whether disruptions of members of the SYNGAP1 Protein interaction network (PIN) can converge on dysregulation of human cortical neurogenesis. This work will be essential for reframing our understanding of the impairments in neural circuit function observed in SYNGAP1 patients by connecting it not only with the well-known alteration in synaptic transmission, but also with early developmental defects. It will also aid the stratification of SYNGAP1 mutations according to their effects on the functionality of the SYNGAP1 PDZ-ligand and the RASGAP domain at early stages of human brain development. Finally, by identifying the SYNGAP1 PIN in early brain development, we expect to discover novel signaling hubs associated with NDD that converge on the dysregulation of human cortical neurogenesis which will inform selection and screening of therapeutic targets.