Gene mutations in autism spectrum disorders are known to cause protein overproduction in brain cells. New research from the Scripps Research Institute shows that protein overproduction in microglial cells, immune cells located in the brain, may have the most relevant effect. Microglial cells normally act by engulfing dead or dying cells in the brain and they also trim back unneeded brain synapses during brain development.
Studying mice, the researchers learned that excess protein impinges on microglial cells limiting their ability to prune synapses. Notably, only male mice displayed this faulty mechanism. Those with dysfunctional microglial cells displayed autism-like social behaviors.
These findings provide insights into two well-known observations of ASD in humans: it is much more prevalent in males, and the brains of individuals with ASD commonly possess more synapses than those without the condition.
“Our study suggests that impairments in microglia play a key role in the development of autism behaviors, at least in some cases, and may help explain the higher prevalence of autism disorders in males,” says study senior author Baoji Xu, PhD, professor in the Department of Neuroscience at Scripps Research. “That, in turn, suggests that microglia might be a good target for future drugs that prevent or treat autism spectrum disorders.”
More than 100 gene mutations and variants have been associated with ASD but working out their effects has been slow going. In their research, the Scripps team selected a cluster of autism-linked gene abnormalities accounting for 3 percent of ASD. These mutations are found in the genes PTEN, TSC1, TSC2, and FMR1. Abnormalities in these genes disrupt normal protein production in cells.
Looking to see if certain types of brain cells exhibit excess protein production and ASD-like behaviors, the Scripps researchers created mice with a deficit that leads to elevated elF4E, a protein production factor. Prior research suggests high levels elF4E may be a by-product of PTEN, TSC1, and other autism-associated gene mutations that leads to excess protein development.
The researchers observed excess elF4e levels in microglial cells in the both male and female mice. But, only the male mice displayed ASD-like behaviors, including repetitive behaviors and abnormal social behaviors, as well as cognitive dysfunction. These behaviors were not seen in other brain cells with high levels of elF4e, including neurons or astrocytes.
Further study showed that in young male mice, the microglial cells were much larger and numerous in critical regions of the brain, including the medial prefrontal cortex, the hippocampus, and the striatum. The differences in these brain regions in female mice were not as significant.
Although the affected microglia appeared to have gene activity suggesting an enhanced pruning capacity, in reality those microglia cells lacked the necessary motility to do so. In normal cells, microglia are highly motile, constantly surveying their microenvironment and converging at the site of injury in the brain. The researchers conclude that this impaired motility in microglial cells is the most important factor leading to ASD-like brain changes in the mice.
Because microglia are at the interface between the brain and environment, the team suggests that environmental influences could increase the risk of ASD by altering functional states of microglia in offspring. “Environmental insults, such as microbial infection during pregnancy, lead to the emergence of core ASD symptoms in the adult offspring, especially in males,” they write. “We propose that augmented responses of microglia to biochemical perturbations induced by gene mutations or microbial infection are an important underlying pathogenesis for ASD.” They also plan on looking deeper into causative reasons behind the sex-based differences in protein overproduction in microglial cells.
