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Researchers Work to Solve the Puzzle of Autism

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April is National Autism Awareness Month, and researchers worldwide are working to better understand this complex condition.

Autism AwarenessAccording to the Centers for Disease Control and Prevention, autism spectrum disorder (ASD) affects one in 44 children in the U.S. and is about four times more common in boys than in girls.

There are more than 100 genes implicated in autism, which makes it that much more difficult to find potential causes and treatments.

New research with mice has uncovered some causes and triggers of ASD, as well as potential treatments.

Sleep Disorders and ASD

People with autism spectrum disorder are more likely to have sleep problems—up to 86% compared to 15-21% in the general population. The connection between sleep disorders and ASD has long been noted, but until recently, sleep disorders were thought to be a side effect of ASD, not a cause or a core feature of the condition.

Now, new research shows that the connection may go deeper, and could be related to a malfunctioning body clock.

A team of researchers from the University of Minnesota, the University of Texas, and the Biomedical Research Institute of the Foundation for Research and Technology Hellas in Greece found that the development of ASD could be related to the disruption of a circadian clock gene.

In the study, researchers found that deleting the Bmal1 gene in mouse models of autism can lead to behaviors consistent with ASD, including social impairments, excessive repetitive behaviors, and motor learning disabilities.

The Bmal1 gene is found throughout the human body and is believed to be a critical part of regulating the body’s circadian clock—the 24-hour biological timer that influences daily functions including sleep and metabolism.

The research team plans to expand its investigation to other clock genes that are commonly mutated in subjects with ASD.

In another study at Harvard University, researchers found atypical circadian rhythms in mice carrying mutations in TSC1 or TSC2 genes, which are connected to tuberous sclerosis, a rare genetic condition that leads to an ASD diagnosis in 40-50% of cases.

At Washington State University Spokane, researchers are also investigating autism-sleep connections, including sleep issues related to a mutation in the SHANK3 gene, which has also been connected to ASD. Mice missing the SHANK3 gene had trouble falling asleep even when they were sleep-deprived, and the team thinks that sleep loss might contribute to a later ASD diagnosis by altering the development of the brain.

The Blankie Effect: Familiar Objects in Unfamiliar Environments

The SHANK3 gene is also a target of a research team at the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland, which is looking into how SHANK3 mutations affect behaviors in mice—especially with relation to environmental factors.

In mice with two mutated copies of the SHANK3 gene, being in an unfamiliar environment triggers problems with social engagement and an increase in repetitive behaviors. However, those behaviors are mitigated if the unfamiliar environment contains familiar objects or if the mice have been raised in an enriched environment.

In tests, researchers were able to normalize the behavior of the SHANK3 mice by familiarizing them with objects in the new environment for 10 days before introducing them to the unfamiliar setting, or by raising the mice in group housing with access to toys and exercise wheels.

The discovery could help scientists understand why people with ASD have difficulty dealing with unfamiliar environments or unexpected situations, and suggests that using familiar objects when encountering new environments could minimize or prevent some autistic traits.

The team plans to administer the test to other mouse models of autism to see if other gene mutations lead to the same results.

Inflammation, Mothers, and the Gut-Brain Connection

Many people with ASD experience a high level of gastrointestinal inflammation, and new research from Harvard Medical School and MIT may have discovered why.

Working with mouse models, researchers discovered that infections during pregnancy can affect the development of the fetal brain and lead to autism-like behavioral symptoms in mouse models, as well as a higher susceptibility to gut inflammation.

According to a new study in mice at the Cleveland Clinic’s Genomic Medicine Institute, maternal infections are not the only way inflammation may lead to autism-like traits in the offspring.

The team found that women who are genetically predisposed to inflammation may be more likely to have children with ASD.

There is already a known connection between inflammation in pregnant women and a slightly increased chance of autism in the child. The Cleveland study explored whether the mother’s genes alone could be the cause of higher levels of inflammation, rather than environmental causes such as infection.

The team looked at the PTEN gene, which is thought to account for 2-17% of all autism cases when the gene is mutated.

They developed a mouse model with only one functioning copy of the PTEN gene rather than the usual two, then bred the one-PTEN mice with wildtype mice. The living pups of one-PTEN mothers and wildtype males were more likely to display autism-associated behaviors, even if they had two fully functional PTEN genes. The pups born with one functional copy of PTEN had even more severe autism-like behaviors.

In addition, the one-PTEN mothers were found to have much lower levels of IL-10—a molecule that suppresses inflammation—during pregnancy, and their unborn offspring had lower levels of immune proteins in their livers.

The team plans to test other genes for their connection to inflammation during pregnancy.

A Cancer Drug Shows Promise with ASD

A cancer drug called vorinostat (also known as SAHA), which is commonly used to treat lymphoma, has shown promise in reducing repetitive behaviors and improving memory and sociability in a mouse model of autism.

Researchers at Michigan State University created a mouse model missing both copies of the autism-linked gene ASH1L in their brains. Mice missing ASH1L in their brains show more repetitive behaviors and reduced interest in socializing.

The team then started daily injections of vorinostat in the ASH1L-missing mice and administered a series of behavioral tests. The mice treated with vorinostat showed more sociability, improved memory, and no excessive grooming, but still displayed heightened anxiety behaviors and motor issues.

The researchers plan to continue testing the drug in different life stages of the mice, to see whether the effects are consistent.

Serious Viral Infections in Boys

Scientists may have found a link between severe viral infections in young boys and a later diagnosis of autism spectrum disorder.

To study the possible connection, researchers at the University of California, Los Angeles, simulated an infection in young mice with tuberous sclerosis, a genetic disorder closely associated with autism in people. Later, the male “infected” mice displayed impaired social behavior often found in ASD, such as poor communication skills with other mice and the inability to distinguish between a mouse they had seen before and a stranger mouse.

Supporting the finding is data collected by the University of Chicago about 3.6 million hospitalized children. The data showed that boys later diagnosed with autism were more likely to have been hospitalized with infections between the ages of 1.5 and 4.

The infections themselves are unlikely to cause autism on their own, researchers say, but could be a trigger in males already genetically predisposed to the condition.

The mouse study may explain why this happens. A severe infection could cause the body to over-produce genes that code for microglia, which are the nervous system's primary immune cells. That excess of microglia can affect brain development, which could lead to autism-related social and verbal impairments. Microglia may develop differently in males and females, which would explain why only boys are affected.

When the researchers administered rapamycin—a drug that targets microglia—to the affected mice, the male mice either showed no autism-like social issues after infection, or stopped showing issues that had already begun to develop.

The takeaway, say researchers, is simple: don’t underestimate the long-lasting damage a serious viral infection can do, and vaccinate your kids. In boys who do suffer an early viral infection, it may be possible to treat them so they do not develop autism later.

With many associated symptoms, a wide range of diagnoses, and hundreds of possible causes, autism spectrum disorder is one of the most difficult conditions to understand and treat. Fortunately, researchers’ work with mouse models continues to shed light and offer hope.


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