CNTN5-/+or EHMT2-/+human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks

• Published in: eLife Vol. 8
• Main Authors: Deneault, Eric, Faheem, Muhammad, White, Sean H, Rodrigues, Deivid C, Sun, Song, Wei, Wei, Piekna, Alina, Thompson, Tadeo, Howe, Jennifer L, Chalil, Leon, Kwan, Vickie, Walker, Susan, Pasceri, Peter, Roth, Frederick P, Yuen, Ryan KC, Singh, Karun K, Ellis, James, Scherer, Stephen W
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 12.02.2019; eLife Sciences Publications, Ltd
• Subjects: Adolescent; Adult; Autism; Autistic Disorder - physiopathology; Cells, Cultured; Child; Contactins - deficiency; Contactins - genetics; Contactins - metabolism; CRISPR; Electrophysiological Phenomena; Families & family life; Female; Genes; Genetics; Genetics and Genomics; Genomes; Genomics; Glutamatergic transmission; Heterozygote; Histocompatibility Antigens - genetics; Histocompatibility Antigens - metabolism; Histone-Lysine N-Methyltransferase - deficiency; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humans; Hyperactivity; Immunoglobulins; Induced Pluripotent Stem Cells - physiology; iPSC; Kinesin - genetics; Kinesin - metabolism; Male; Medical research; Middle Aged; Models, Theoretical; Nerve Net - physiology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural networks; Neural stem cells; Neurons - physiology; Neuroscience; NGN2-neurons; Patch-Clamp Techniques; Phenotypes; Pluripotency; Research Communication; Stem cells; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Young Adult; Zinc Finger Protein Gli3 - genetics; Zinc Finger Protein Gli3 - metabolism; Canada; United States > US; CRISPR; genetics; neuroscience; iPSC; genomics; human; NGN2-neurons; autism
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.40092

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. 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. Editorial note: This article has been through an editorial process in which authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter ).