Autism Spectrum Disorder Induced Pluripotent Stem Cells Display Dysregulated Calcium Signaling During Neural Differentiation.

Scientists grew brain cells from people with autism and compared them to typical brain cells. They found that calcium - an important chemical messenger in brain cells - works differently in autism cells. At early stages, autism cells showed too much calcium activity. At later stages when cells became more like neurons, they showed different patterns of calcium responses depending on what triggered them. This suggests calcium problems might contribute to how autism develops in the brain.

This study used induced pluripotent stem cells (iPSCs) from autistic individuals and controls to investigate calcium signaling during neural development. Researchers differentiated these cells into cortical neurons and analyzed gene expression and calcium responses at different stages. Transcriptomic analysis revealed more calcium signaling-related gene differences between autism and control samples at the iPSC and differentiated neuron stages. Functional calcium imaging showed autism samples had elevated calcium responses to ATP at the iPSC stage, but altered patterns at the neuron stage - reduced ATP responses yet increased responses to KCl and DHPG stimuli.

These findings suggest calcium homeostasis dysregulation may underlie autism pathophysiology during brain development.

Findings suggest calcium signaling pathways may be therapeutic targets for autism. However, translation to clinical applications requires further research. Results support the biological basis of autism involving cellular communication defects during brain development.

Sample size not reported. Study limited to idiopathic autism cases. In vitro model may not fully represent in vivo brain development. Unclear how findings translate to clinical outcomes or symptoms.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects communication, social interaction, and behavior. Calcium (Ca) signaling dysregulation has been frequently highlighted in genetic studies as a contributing factor to aberrant developmental processes in ASD. Herein, we used ASD and control induced pluripotent stem cells (iPSCs) to investigate transcriptomic and functional Cadynamics at various stages of differentiation to cortical neurons. Idiopathic ASD and control iPSC lines underwent the dual SMAD inhibition differentiation protocol to direct their fate toward cortical neurons.

Samples from multiple time points along the course of differentiation were processed for bulk RNA sequencing, spanning the following sequential stages: the iPSC stage, neural induction (NI) stage, neurosphere (NSP) stage, and differentiated cortical neuron (Diff) stage. Our transcriptomic analyses suggested that the numbers of Casignaling-relevant differentially expressed genes between ASD and control samples were higher in the iPSC and Diff stages. Accordingly, samples from the iPSC and Diff stages were processed for Caimaging studies. Results revealed that iPSC-stage ASD samples displayed elevated maximum Calevels in response to ATP compared to controls.

By contrast, in the Diff stage, ASD neurons showed reduced maximum Calevels in response to ATP but increased maximum Calevels in response to KCl and DHPG relative to controls. Considering the distinct functional signaling contexts of these stimuli, this differential profile of receptor- and ionophore-mediated Caresponse suggests that aberrant calcium homeostasis underlies the pathophysiology of ASD neurons. Our data provides functional evidence for Casignaling dysregulation during neurogenesis in idiopathic ASD.