Dataset Information

Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis.

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.

SUBMITTER: Birtele M

PROVIDER: S-EPMC11349286 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis.

Birtele Marcella M Del Dosso Ashley A Xu Tiantian T Nguyen Tuan T Wilkinson Brent B Hosseini Negar N Nguyen Sarah S Urenda Jean-Paul JP Knight Gavin G Rojas Camilo C Flores Ilse I Atamian Alexander A Moore Roger R Sharma Ritin R Pirrotte Patrick P Ashton Randolph S RS Huang Eric J EJ Rumbaugh Gavin G Coba Marcelo P MP Quadrato Giorgia G

Nature neuroscience 20231109 12

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 ...[more]

PMID: 37946050

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Project description:Recent longitudinal neuroimaging and neurophysiological studies have shown that tracking relative age-related changes in neural signals, rather than a static snapshot of a neural measure, could offer higher sensitivity for discriminating typically developing (TD) individuals from those with autism spectrum disorder (ASD). It is not clear, however, which aspects of age-related changes (trajectories) would be optimal for identifying atypical brain development in ASD. Using a large cross-sectional data set (Autism Brain Imaging Data Exchange [ABIDE] repository; releases I and II), we aimed to explore age-related changes in cortical thickness (CT) in TD and ASD populations (age range 6-30 years old). Cortical thickness was estimated from T1-weighted MRI images at three scales of spatial coarseness (three parcellations with different numbers of regions of interest). For each parcellation, three polynomial models of age-related changes in CT were tested. Specifically, to characterize alterations in CT trajectories, we compared the linear slope, curvature, and aberrancy of CT trajectories across experimental groups, which was estimated using linear, quadratic, and cubic polynomial models, respectively. Also, we explored associations between age-related changes with ASD symptomatology quantified as the Autism Diagnostic Observation Schedule (ADOS) scores. While no overall group differences in cortical thickness were observed across the entire age range, ASD and TD populations were different in terms of age-related changes, which were located primarily in frontal and tempo-parietal areas. These atypical age-related changes were also associated with ADOS scores in the ASD group and used to predict ASD from TD development. These results indicate that the curvature is the most reliable feature for localizing brain areas developmentally atypical in ASD with a more pronounced effect with symptomatology and is the most sensitive in predicting ASD development.

Dataset Information

Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis.

Publications

Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis.

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