Search

Individuals with Williams syndrome (WS), a multisystemic neurodevelopmental disorder, characteristically portray a hypersocial phenotype. WS is caused by the hemizygous loss of ~26 genes at chromosomal locus 7q11.23, one of which is GTF2I. Copy number variations and mutations in GTF2I are associated with altered sociality and have been proposed to underlie the hypersocial expression of WS. However, the contribution of GTF2I to human neurodevelopment remains incompletely understood. Here, human cellular models of neurodevelopment, including neural progenitors, neurons, and three-dimensional cortical organoids, were differentiated from CRISPR-Cas9-edited GTF2I-knockout (GTF2I-KO) isogenic pluripotent stem cells (hiPSCs) to investigate the role of GTF2I in human neurodevelopment. Compared to controls, GTF2I-KO progenitors exhibited an increased proliferation rate and an altered cell cycle profile. Cortical organoids and neurons demonstrated increased cell death and synaptic dysregulation, including synaptic structural dysfunction and electrophysiological impairment on multi-electrode array. Overall, our findings show loss of GTF2I promotes synaptic defects, increased cell death, and impaired neuronal network function in human cellular models of neurodevelopment, suggesting changes in synaptic circuit integrity may be a prominent mediator of the link between alterations in GTF2I and variation in the phenotypic expression of human sociality.

Prenatal alcohol exposure (PAE) is one of the leading preventable causes behind neurodevelopmental disorders- underlying intellectual disability, cognitive dysfunction, and numerous defects found within Fetal Alcohol Spectrum Disorder (FASD). Alcohol impacts diverse neural cell types; however, more specific pathophysiological effects on the human fetal cerebral cortex remain unclear. Here, we used cortical organoids, astrocytes, and primary fetal neurons to explore cellular alterations induced by ethanol exposure. Within our human neural models, EtOH altered apoptosis, cell cycle, and proliferation. Additionally, expression of co-localized synaptic puncta markers and synaptic proteins was reduced from early ethanol treatment. To potentially rescue these synaptic alterations, four drug compounds were employed; Donepezil, an acetylcholinesterase inhibitor commonly used to treat Alzheimer’s and dementia, produced promising results for improving synaptic expression. Our study contributes to preliminary neurodevelopmental modeling of PAE- further defining cellular phenotypic signatures and elucidating potential therapeutic options.

Due to the cyclical nature of selective pressures in our physical world, most organisms evolved endogenous circadian timing systems that generate circadian rhythms in behavior and physiology. External stimuli such as light can reset these rhythms allowing the synchronization of the body with the external environment. Symptoms of disrupted circadian systems are comorbid with both neurodegenerative and neurodevelopmental disease states. Deficits in the ability of light information to reach the circadian system may provide a mechanistic explanation for the deregulated circadian system. Our study investigated the presence of deficits in the light input pathway to the circadian system in Huntington’s Disease (HD) and Fragile X Syndrome (FXS) mouse models. We found that the ability of light information to reach the circadian system is not altered in these models and the observed circadian dysfunction may be due to an underlying pathology present in the central circadian circuit.