Abstract：
:Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt-Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. 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. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.
journal_name
Nat Neuroscijournal_title
Nature neuroscienceauthors
Phan BN,Bohlen JF,Davis BA,Ye Z,Chen HY,Mayfield B,Sripathy SR,Cerceo Page S,Campbell MN,Smith HL,Gallop D,Kim H,Thaxton CL,Simon JM,Burke EE,Shin JH,Kennedy AJ,Sweatt JD,Philpot BD,Jaffe AE,Maher BJdoi
10.1038/s41593-019-0578-xsubject
Has Abstractpub_date
2020-03-01 00:00:00pages
375-385issue
3eissn
1097-6256issn
1546-1726pii
10.1038/s41593-019-0578-xjournal_volume
23pub_type
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