Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis.
Publication Year:
2023
PubMed ID:
37946050
Funding Grants:
Public Summary:
Autism spectrum disorder (ASD) is often linked to rare genetic changes in genes that help neurons communicate at synapses. However, many ASD-related brain changes happen before synapses even form, and it has been unclear how these “synaptic” genes contribute. This study focused on one such gene, SYNGAP1, and found that it is active in early brain stem cells called radial glia. When SYNGAP1 function is reduced, these cells show abnormal structure and division, leading to disorganized layers in the developing cortex and faster-than-normal maturation of certain neurons. Similar imbalances between progenitor cells and neurons were seen in mice with reduced SYNGAP1. These findings suggest that some SYNGAP1-related brain disorders may arise through early developmental changes, not just problems at synapses, highlighting the importance of studying ASD genes across different cell types and stages of brain development.
Scientific Abstract:
Genes involved in synaptic function are enriched among those with autism spectrum disorder (ASD)-associated rare genetic variants. Dysregulated cortical neurogenesis has been implicated as a convergent mechanism in ASD pathophysiology, yet it remains unknown how 'synaptic' ASD risk genes contribute to these phenotypes, which arise before synaptogenesis. Here, we show that the synaptic Ras GTPase-activating (RASGAP) protein 1 (SYNGAP1, a top ASD risk gene) is expressed within the apical domain of human radial glia cells (hRGCs). In a human cortical organoid model of SYNGAP1 haploinsufficiency, we find dysregulated cytoskeletal dynamics that impair the scaffolding and division plane of hRGCs, resulting in disrupted lamination and accelerated maturation of cortical projection neurons. Additionally, we confirmed an imbalance in the ratio of progenitors to neurons in a mouse model of Syngap1 haploinsufficiency. Thus, SYNGAP1-related brain disorders may arise through non-synaptic mechanisms, highlighting the need to study genes associated with neurodevelopmental disorders (NDDs) in diverse human cell types and developmental stages.
