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Neurons derived from induced pluripotent stem cells are used more broadly to model the spectrum disorder of autism, which is heterogeneous in clinical and genetic terms. In this study, scientists describe the impacts of neuronal mutation on the characteristics of autism in humans published in eLife.
To investigate the complex relationships of lower penetrating and polygenic risk variants with neurons derived from the isogenic iPSC protein of the autism spectrum disorder. A set of procedures to control the heterogeneity of reprogramming and differentiation were developed to generate 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with autism spectrum disorders.
According to the researchers "Hematozygous variants of de novo and suspected inherited damaging variants have been characterized in genes / loci at risk for autism spectrum disorders; combinations of suspected etiological variants belonging to distinct families were modeled using a multi-electrode array with patch-clamp recordings to determine a reproducible synaptic phenotype in 25% of participants with autism spectrum disorder. The most convincing results reveal a network of coherent spontaneous hyperactivity in neurons deficient in EHMT2 or CNTN5; and the biobank of iPSC-derived neurons as well as the corresponding genomic data have been made openly available to accelerate research on ASDs, which should help accelerate the development of new therapeutic strategies. "
IPSCs are increasingly being used to study ASD and treatment responses. However, high costs generally mean that only a few neuronal lineages derived from iPSC are used in a single study that limits research and imposes new approaches to accelerate developments in this area.
In collaboration, researchers from McMaster University, the University of Toronto and the Hospital for Sick Children in Canada have decided to develop iPSC-derived evolutionary neuron models to help to the progress of research on autism. A resource of 53 different iPSC lines derived from 25 autism patients who carried a wide range of rare genetic variants and unaffected family members was developed. Using CRISPR editing, 4 isogenic pairs of non-mutation and non-mutation iPSC lines were also created to explore the effects of mutation on autistic characteristics.
Eric Deneault, PhD, studied the synaptic and electrophysiological properties of iPSC lines using a large-scale multi-electrode array for neuronal recordings as well as traditional patch-clamp recordings. The results revealed numerous badociations between the genetic variants and the neuronal characteristics badyzed.
Deneault's most compelling conclusion was the persistent spontaneous network hyperactivity in neurons deficient in EHMT2 or CNTN5 genes that may cause autistic characteristics; the discovery matches the current views and opens the way for further investigation into their roles in ASD.
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