Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder.

Jun Ju,Lei Zheng,Jian Jiang,Dilong Wang,Sheng-Tao Hou,Xiuyan Yang,Yumeng Zhang,Xiaofeng Zhao,Yihang Pan,Xiaoyi Fang,Ningning Li,Liyang Liang,Huiliang Li,Huanquan Liao,Shupeng Li

doi:10.3389/fncel.2021.718720

Abstract

Myelin abnormalities have been observed in autism spectrum disorder (ASD). In this study, we seek to discover myelin-related changes in the striatum, a key brain region responsible for core ASD features, using the 16p11.2 deletion (16p11.2±) mouse model of ASD. We found downregulated expression of multiple myelin genes and decreased myelin thickness in the striatum of 16p11.2± mice versus wild type controls. Moreover, given that myelin is the main reservoir of brain lipids and that increasing evidence has linked dysregulation of lipid metabolism to ASD, we performed lipidomic analysis and discovered decreased levels of certain species of sphingomyelin, hexosyl ceramide and their common precursor, ceramide, in 16p11.2± striatum, all of which are major myelin components. We further identified lack of ceramide synthase 2 as the possible reason behind the decrease in these lipid species. Taken together, our data suggest a role for myelin and myelin lipids in ASD development.

Highlights

Autism spectrum disorder (ASD) is a developmental disorder characterized by social communication difficulties, restricted interests, repetitive behaviors and intellectual disability (Lyall et al, 2017)
RNA Sequencing (RNAseq) data analysis revealed that the expression of multiple myelin-related genes was significantly decreased in the striatum of 16p11.2± mice compared to wide type (WT) controls, including myelin associated glycoprotein (Mag, p < 0.05), myelin oligodendrocyte glycoprotein (Mog, p < 0.05), myelin basic protein (Mbp, p < 0.01), proteolipid protein 1 (Plp1, p < 0.05) (Figure 1A)
We found downregulated expression of a number of myelin genes (Figure 1) and altered myelin microstructure (Figure 2) in the striatum of 16p11.2± mice, a Copy number variation (CNV) animal model of ASD

Summary

Introduction

Autism spectrum disorder (ASD) is a developmental disorder characterized by social communication difficulties, restricted interests, repetitive behaviors and intellectual disability (Lyall et al, 2017). The prevalence of ASD is estimated at 0.76% (i.e., 1 in 132 people) globally (Baxter et al, 2015) and around 12.8 per 1000 population in China (Wan et al, 2013). The exact cause remains poorly understood, ASD is believed to result from a combination of genetic and environmental factors (Muhle et al, 2004). Copy number variation (CNV), which results in submicroscopic alterations to chromosome structure, represents another genetic risk factor for ASD (Sebat et al, 2007). CNV involving a ∼600kb DNA segment at the chromosome 16p11.2 locus has been strongly linked to ASD, and 16p11.2 deletion is one of the most frequently observed cytogenetic causes of ASD with an estimated prevalence of 0.5% among ASD patients (Chung et al, 2021)

Methods

Results

Conclusion