A myelin-related transcriptomic profile is shared by Pitt-Hopkins syndrome models and human autism spectrum disorder.

Abstract

Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. We analyzed brain transcriptional changes in five mouse models of Pitt-Hopkins Syndrome (PTHS), a syndromic form of ASD caused by mutations in TCF4 (transcription factor 4, not TCF7L2 / T-Cell Factor 4). Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4 and Mecp2tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. Next, we integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-seq data, and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Importantly, DEGs from syndromic ASD mouse models, and reduced deconvoluted OL numbers, distinguished human idiopathic ASD cases from controls across three postmortem brain datasets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.