Autism Associated Gene Deficiencies Linked To Neuronal Hyperactivity

To investigate complex relationships of penetrant and weaker polygenic risk variants to Autism Spectrum Disorder isogenic iPSC-derived neurons are crucial; a set of procedures to control for heterogeneity in reprogramming and differentiation were developed to generate 53 different iPSC derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with Autism Spectrum Disorder.

According to the researchers “Heterozygous de novo and rare inherited presumed damaging variants were characterized in Autism Spectrum Disorder risk genes/loci; combinations of putative etiologic variants in seperate families were modeled using a multi-electrode array with patch clamp recordings to determine a reproducible synaptic phenotype in 25% of the participants with Autism Spectrum Disorder. Most compelling results reveal a consistent spontaneous network of hyperactivity in neurons deficient for EHMT2 or CNTN5; and the biobank of iPSC derived neurons along with accompanying genomic data has been made openly available to accelerate ASD research which is hoped to speed up development of new therapeutic strategies.”

IPSCs are being used to study ASD and responses to treatments increasingly, however high costs typically mean only a few iPSC derived neuronal lines are used in a single study which limits research, making new approaches needed to speed up developments in this area.

In collaboration researchers from McMaster University, the University of Toronto, and The Hospital for Sick Children in Canada set out to establish scalable iPSC derived neuron models to help further and improve autism research. A resource of 53 different iPSC lines derived from 25 patients with autism who carried a wide range of rare genetic variants, and from their unaffected family members was developed. Using CRISPR editing 4 isogenic pairs of iPSC lines that had or did not have a mutation were also created to explore impacts of mutation on autistic characteristics.

Synaptic and electrophysiological properties on the iPSC lines were investigated using a large scale multi-electrode array for neuronal recordings along with traditional patch clamp recordings explains Eric Deneault, PhD. Results revealed numerous associations between genetic variants and neuronal characteristics that were analyzed.

Most compelling finding according to Deneault was the consistent spontaneous network hyperactivity in neurons deficient in EHMT2 or CNTN5 genes which may cause autistic characteristics; discovery is consistent with current views and paves the way for further investigations of their roles in ASD.