Defects of myelination are common pathophysiology in syndromic and idiopathic autism spectrum disorder

Abstract

Autism Spectrum Disorder (ASD) is genetically heterogeneous in nature with convergent symptomatology, suggesting dysregulation of common molecular pathways. We analyzed transcriptional changes in the brains of five independent mouse models of Pitt-Hopkins Syndrome (PTHS), a syndromic ASD caused by autosomal dominant mutation in TCF4, and identified considerable overlap in differentially expressed genes (DEGs). Gene and cell-type enrichment analyses of these DEGs identified oligodendrocyte dysregulation that was subsequently validated by decreased protein levels. We further showed significant enrichment of myelination genes was prevalent in two additional mouse models of ASD (Pten m3m4/m3m4 , Mecp2 KO ). Moreover, we integrated syndromic ASD mouse model DEGs with ASD risk-gene sets (SFARI) and human idiopathic ASD postmortem brain RNA-seq and found significant enrichment of overlapping DEGs and common biological pathways associated with myelination and oligodendrocyte differentiation. These results from seven independent mouse models are validated in human brain, implicating disruptions in myelination is a common ASD pathophysiology.Main Text: Autism spectrum disorder (ASD) affects approximately 1:68 individuals and has incalculable burdens on affected individuals, their families, and health care systems. While the genetic contributions to idiopathic ASD are heterogeneous and largely unknown, the causal mutations for syndromic forms of ASD -including truncations and copy number variantsprovide a genetic toehold with which to gain mechanistic insights(1-3). Models of these syndromic disorders have been used to better characterize the molecular and physiological processes disrupted by these mutations(4). Two fundamental questions remain -how . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/128124 doi: bioRxiv preprint first posted online Apr. 18, 2017; 3 biologically similar are the mouse models of syndromic forms of ASD, and how relevant are these mouse models to their human analogs? To address these questions, we performed integrative transcriptomic analyses of seven independent mouse models of three syndromic forms of ASD generated across five laboratories, and assessed dysregulated genes and their pathways in human postmortem brain from patients with ASD and unaffected controls. These cross-species analyses converged on shared disruptions in myelination and axon development across both syndromic and idiopathic ASD, highlighting both the face validity of mouse models for these disorders and identifying novel convergent molecular phenotypes amendable to rescue with therapeutics.We first assessed molecular convergence across five different mouse models of Pitt-Hopkins syndrome (PTHS), a rare form of ASD that results from diverse mutations in the transcription factor 4 (TCF4) gene, ranging from haploinsufficiency to dominant-negative. This syndromic disorder is cha...

The Neurodevelopment of Autism from Infancy Through Toddlerhood

“…Alterations in corpus callosum morphology and in the development of white matter microstructure in early ASD implicates processes governing myelination, axon caliber, density and axonal connectivity. A study of several mouse models of ASD recently identified a significant enrichment of myelination genes, and gene-set analysis implicated genes and pathways associated with myelination and oligodendrocyte differentiation 139 . Altered oligodendrocyte function has been documented in Pten-mutant mouse models of ASD, such that oligodendrocyte progenitor cells developed too early, resulting in reduced myelin sheaths 140 , which would impede information transfer along axons.…”