Autism-Associated Gene Deficiencies Linked to Neuronal Hyperactivity

Scientists have described the impacts of neuronal mutations on autism-related characteristics in humans in an open-access article (“CNTN5-/+or EHMT2-/+human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks”) published recently in eLife.

“Induced pluripotent stem cell (iPSC)-derived neurons are increasingly used to model Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of penetrant and weaker polygenic risk variants to ASD, ‘isogenic’ iPSC-derived neurons are critical. We developed a set of procedures to control for heterogeneity in reprogramming and differentiation, and generated 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with ASD,” wrote the investigators.

“Heterozygous de novo and rare-inherited presumed-damaging variants were characterized in ASD risk genes/loci. Combinations of putative etiologic variants (GLI3/KIF21A or EHMT2/UBE2I) in separate families were modeled. We used a multi-electrode array, with patch-clamp recordings, to determine a reproducible synaptic phenotype in 25% of the individuals with ASD (other relevant data on the remaining lines was collected). Our most compelling new results revealed a consistent spontaneous network hyperactivity in neurons deficient for CNTN5 or EHMT2. The biobank of iPSC-derived neurons and accompanying genomic data are available to accelerate ASD research.”

Autism spectrum disorder, and autism patients’ responses to treatments, is increasingly studied using neurons derived from iPSCs. But high costs mean that only a few iPSC-derived neuronal lines are typically tested in a single study, limiting previous autism research. New approaches are therefore needed to speed up developments in this area.

A team of researchers from The Hospital for Sick Children (SickKids), the University of Toronto, and McMaster University in Canada set out to establish a scalable iPSC-derived neuron model to help improve autism research. They developed a resource of 53 different iPSC lines derived from 25 individuals with autism, who carry a wide range of rare genetic variants, and from their unaffected family members.

Using CRISPR editing, the scientists also created four “isogenic” pairs of iPSC lines that either had or did not have a mutation, to explore the impacts of mutations on autistic characteristics.

“We investigated the synaptic and electrophysiological properties of our iPSC lines using a large-scale multi-electrode array for neuronal recordings, as well as more traditional patch-clamp recordings,” explained first author Eric Deneault, PhD, postdoctoral fellow previously in the genetics and genome biology program at SickKids, and now at the Montreal Neurological Institute, McGill University. “Our results revealed numerous interesting associations between the genetic variants and the neuronal characteristics that we analyzed.”

Deneault says their most compelling find was a consistent, spontaneous network hyperactivity in neurons that were deficient in the CNTN5 or EHMT2 genes, which may cause autistic characteristics in people. This discovery of hyperactive networks is consistent with current views of autism and paves the way for further investigating their roles in the condition.

“In fact, we have made our biobank of iPSC-derived neurons and accompanying genomic data openly available to help accelerate research in this area,” said Stephen Scherer, PhD, a co-senior author of the paper and director of The Centre for Applied Genomics at SickKids, and of the McLaughlin Centre at the University of Toronto. “We hope this will in turn speed up the development of potential new therapeutic strategies for autism patients.”

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