Nature Communications: The Relationship between Autism in Men and Small Glial Cell Defects, or The Mystery of Gender Differences in Autism

Autism (ASD), also known as autism spectrum disorder, has long puzzled scientists for the "difference between men and women." In 2014, the idea that men's brains were more susceptible to genetic defects was partially positive, and the study now looks at neuronal function as a starting pointUnderstanding the gender differences in autism is essential for timely and correct diagnosis, but more crucially, it is likely to signal the direction of future drug developmentso far, scientists know little about how small glial cell pruning affects brain developmentA 2010 study found that nine of the 13 brain samples had large-scale dense and active small glial cells, and another study in 2014 showed that mice with fewer small glial cells in the brain early in life showed autistic behaviorSimon Baron Cohen, director of the Centre for Autism Studies at the University of Cambridge, said the latest work by the Walling team was consistent with other findings that brain changes in autism may have occurred before birthIn 2017, the team of neurobiologists at the University of California, San Francisco, found that genes associated with small glial cells were more active in boys' brains than in girls, suggesting that there was a fundamental difference in brain development in boys and girlsrecently, a new study led by scientists at the Scripps Research Institute suggests that many conditions of ASD may be caused by problems with immune cells, which can often reduce unnecessary brain connections early in lifeThe study, published Tuesday in nature communications, looked at the effects of a group of genetic mutations that make up only a small fraction of autismThese mutations are known to cause widespread overproduction of many proteins in brain cells, but how this overdose causes autism has been a mysteryscientists have found evidence that the most relevant effects of overproduction of the protein occur in brain immune cells called small glial cellsThese cells usually prune unwanted brain connections or synapses as the brain develops in childhoodBy studying mice, scientists determined that overproduction of proteins could damage small glial cells, which could impair synaptic pruning, but only in men, leading to autism-like social behavior disordersthe findings coincide with long-standing observations that men are four to five times more likely to have autism than womenThis is consistent with recent evidence that people with ASD usually have more synapses in their brains than normal peoplestudies have shown that damage to small glial cells plays a key role in the development of autism behavior, at least in some cases, may help explain the increased prevalence of autism in menThis, in turn, suggests that small glial cells may be good targets for the prevention or treatment of future asD drugsestimates that 2.4 per cent of men and 0.5 per cent of women have ASDThey involve a variety of behavioral disorders, including insufficient social skills, repetitive behavior, and extreme sensitivity to sound and lightStudies have shown that these behavioral disorders are largely hereditary, but may be caused by abnormalities in many different genes, either individually or in combinationTo date, more than 100 gene mutations and variants have been associated with ASDa group of autism-related genetic abnormalities (including mutations in the genes PTEN, TSC1, TSC2 and FMR1) accounted for about 3% of ASD casesThe combined effect of these abnormalities is to disrupt the way protein production levels are usually regulated in cells, thereby increasing protein productionresearchers try to determine whether there is a specific cell type in the brain that could explain the link between increased protein production and ASD-like behaviorThey engineered the mice to produce only one cell type at a time, an abnormally high level of protein production factor called eIF4EHigh levels of eIF4E are considered to be one of the most common events that connect PTEN, TSC1, and other autism mutations (increasing protein production)When high eIF4E levels occurred in small glial cells, the social behavior, cognitive impairment, and repetitive behavior of mice showed ASD-like abnormalities, but ASD-type abnormalities occurred only in male miceWhen high eIF4E levels occur in neurons or auxiliary cells called astrocytes, no similar behavioral abnormalities are seen at allresearchers examined the affected small glial cells for clues as to how elevated protein synthesis levels in those cells could lead to changes in ASD-like behaviorThey found that in male mice, the small glial cells of important brain regions, including the inner frontal cortex, hippocampus and striatum, were significantly larger and larger, while in females, these changes were more subtle and transientsmall glial cells often trim unused or unwanted synapses during brain developmentThe researchers found that in male ASD-like male mice with elevated glial eIF4E, there were more synapses than normal, suggesting that the pattern of "trim defects" was also prevalent in people with autismsmall glial cells in mice showed a pattern of genetic activity, indicating an increased ability to trim synapses However, experiments have also shown that these cells lack the usual motor or motor abilities, which prevents them from performing synaptic pruning The researchers suspect that the reduction in the vitality of small glial cells may be the most important factor, so in general, the cell's synaptic pruning ability is impaired, leading to brain changes similar to ASD now, researchers are following up on research to find out exactly why protein increases affect small glial cells in men far more than women The findings could prove to be an important part of the mystery of the gender differences in autism, and could set new goals for autism treatment references: Zhi-Xiang Xu, et al.
Elevated protein synthesis in microglia causes autism-like synaptic and ablin aberrations Nature Communications (2020) Author: Name Source: