Abstract Autism spectrum disorder (ASD) is a genetically heterogeneous disorder linked with rare, inherited and de novo mutations occurring in two main functional gene categories: gene expression regulation and synaptic function 1 . Accumulating evidence points to dysregulation in cortical neurogenesis as a convergent mechanism in ASD pathophysiology 2-8 . While asynchronous development has been identified as a shared feature among ASD-risk genes in the category of gene expression regulation, it remains unknown whether this phenotype is also associated with ASD-risk genes in the synaptic function category. Here we show for the first time the expression of the synaptic Ras GTP-ase activating protein 1 (SYNGAP1), one of the top ASD risk genes 9 , in human cortical progenitors (hCPs). Interestingly, we found that multiple components of the postsynaptic density (PSD) of excitatory synapses, of which SYNGAP1 is one of the most abundant components 10,11 , are enriched in the proteome of hCPs. Specifically, we discover that SYNGAP1 is expressed within the apical domain of human radial glia cells (hRGCs) where it lines the wall of the developing cortical ventricular zone colocalizing with the tight junction-associated protein and MAGUK family member TJP1. In a cortical organoid model of SYNGAP1 haploinsufficiency, we show dysregulated cytoskeletal dynamics that impair the scaffolding and division plane of hRGCs, resulting in disrupted lamination of the cortical plate and accelerated maturation of cortical projection neurons. Overall, the discovery of the expression and function of SYNGAP1 in cortical progenitor cells reframes our understanding of the pathophysiology of SYNGAP1-related disorders and, more broadly, underscores the importance of dissecting the role of synaptic genes associated with neurodevelopmental disorders in distinct cell types across developmental stages.

The autism-associated gene SYNGAP1 regulates human cortical neurogenesis