Hypomyelination and Oligodendroglial Alterations in a Mouse Model of Autism Spectrum Disorder

Abstract

Autism spectrum disorders (ASDs) are neuropsychiatric diseases characterized by impaired social interaction, communication deficits, and repetitive and stereotyped behaviors. ASD etiology is unknown, and both genetic and environmental causes have been proposed. Different brain structures are believed to play a role in ASD-related behaviors, including medial prefrontal cortex (mPFC), hippocampus, piriform cortex (Pir), basolateral amygdala (BLA) and Cerebellum. Compelling evidence suggests a link between white matter modifications and ASD symptoms in patients. Besides, an hypomyelination of the mPFC has been associated in rodents to social behavior impairment, one of the main symptoms of ASD. However, a comparative analysis of myelination as well as oligodendroglial (OL)-lineage cells in brain regions associated to social behaviors in animal models of ASD has not been performed so far. Here, we investigated whether OL-lineage cells and myelination are altered in a murine model of ASD induced by the prenatal exposure to valproic acid (VPA). We showed an hypomyelination in the BLA and Pir of adult VPA-exposed mice. These results were accompanied by a decrease in the number of OL-lineage cells and of mature OLs in the Pir, in addition to the mPFC, where myelination presented no alterations. In these regions the number of oligodendrocyte progenitors (OPCs) remained unaltered. Likewise, activation of histone deacetylases (HDACs) on OL-lineage cells in adulthood showed no differences. Overall, our results reveal OL-lineage cell alterations and hypomyelination as neuropathological hallmarks of ASD that have been overlooked so far.

Examining the boundary sharpness coefficient as an index of cortical microstructure and its relationship to age and sex in autism spectrum disorder

“…This assumption is supported by the general agreement between the group-average BSC map ( Supplementary Fig. S8) and the intracortical myelin map derived using the T1w/T2w ratio by Glasser and Van Essen (Glasser and Van Essen 2011) and is further supported by evidence from studies suggesting altered intracortical myelination in ASD, including genetic (Richetto et al 2017) and molecular (Lee et al 2019;Canali et al 2018) studies, preclinical mouse models (Graciarena et al 2018;Shen et al 2018) , and postmortem histology (Zikopoulos and Barbas 2010) . Furthermore, age-related effects of BSC in healthy controls (Supplementary Figure S3) recapitulate normative developmental patterns of intracortical myelination.…”

Morphometric Analysis of the Corpus Callosum According to Age and Sex in Middle Eastern Arabs: Racial Comparisons and Clinical Correlations to Autism Spectrum Disorder

“…In addition, they found the reduced fiber density in the region of the splenium to be associated with greater social impairment. With regard to myelination, there is a mounting evidence from the literature suggesting that autism is associated with hypomyelination and oligodendrocyte dysfunction (Wei et al, 2016;Kamata et al, 2017;Shen et al, 2018;Graciarena et al, 2019). A genomic-wide transcriptional study demonstrated defects in myelin stability and functionality genes in autism (Richetto et al, 2017).…”

“…A genomic-wide transcriptional study demonstrated defects in myelin stability and functionality genes in autism (Richetto et al, 2017). In addition, hypomyelination has been detected in different animal models of autism, including BTBR mice (Wei et al, 2016), mice exposed to valproic acid prenatally (Graciarena et al, 2019), and rats who had been exposed to both fetal inflammation and postnatal hypoxia (van Tilborg et al, 2018). Nevertheless, further studies are required to determine the exact nature of the reduction of CC size in patients with ASD and whether this reduction has a causative or associative relation to autism.…”

Myelin Pathology Beyond White Matter in Tuberous Sclerosis Complex (TSC) Cortical Tubers

“…Shepherd et al indicated an association between white matter reduction and duration of epilepsy and studies in patients with temporal lobe epilepsy and mild malformations of cortical development showed an increased number of oligodendroglia compared with controls ( 16 , 20 ). Hypomyelination and alteration of oligodendroglia in the prefrontal cortex have been reported as neuropathological hallmarks of autism spectrum disorder (ASD) ( 21 ).…”