SFARI Research Roundup SFARI Research Roundup

Annual Report

2017 Edition

SFARI Research Roundup

Over the past 15 years, the Simons Foundation Autism Research Initiative (SFARI) has supported more than 400 researchers studying autism and related disorders. In 2017 alone, SFARI provided funding to more than 200 investigators from around the world, who have studied everything from sex differences in a mouse model of autism to the role of maternal gut bacteria in the condition. The following are some highlights of the research of SFARI Investigators in 2017.

Making sense of missense

Researchers have uncovered 200 candidate risk genes for autism and other neurodevelopmental conditions by examining ‘missense’ mutations — mutations that change only one nucleotide in a gene, but in a way that alters the resulting protein. Even though missense mutations are thought to account for more cases of autism than more damaging mutations called ‘likely gene-disruptive’ mutations, they have been studied far less, partly because they are so common in the general population that disentangling their role in autism is tricky.

Now, a team led by SFARI Investigator Evan Eichler of the University of Washington has analyzed missense mutations in 8,477 people with neurodevelopmental conditions, along with 2,178 controls. The team found 200 genes that have significantly more missense mutations in individuals with a neurodevelopmental condition than in controls; 79 percent of these genes have never before been associated with a neurodevelopmental condition. One of the most frequently appearing missense mutations was found in a gene called GRIA1, which encodes a receptor for a neurotransmitter called glutamate.

The study’s techniques, described in the August 2017 issue of Nature Neuroscience, offer a way not just to identify candidate risk genes, but also to pinpoint just which parts of a gene confer the most risk if they are mutated. This information may prove valuable down the road when it comes to designing targeted therapies for autism and other neurodevelopmental conditions.

Preferred parents

People and animals have two copies of most genes — one copy from each parent — and conventional wisdom says that the two copies are expressed equally in the body. Yet studies of cultured cells have indicated that this may not always be the case. Now a study published March 8, 2017, in Neuron has shown for the first time that this conventional wisdom is not true in the brains of mice, monkeys and humans.

SFARI Investigator Christopher Gregg, of the University of Utah in Salt Lake City, and his collaborators found that mouse livers and muscle tissues and a brain region called the dorsal raphe nucleus all have some genes that preferentially express a particular parent’s copy. When the researchers mutated one parental copy of one of these genes, they found patches of expression of the mutated gene throughout the mouse brain. The team also found genes with parental preferences in macaque monkeys and in postmortem human brains.

Several of the genes identified in macaques are associated with autism, and others are linked to bipolar disorder, intellectual disability or other neurodevelopmental conditions. Among the autism genes, one of two parental copies of DEAF1 is also preferentially expressed in four human brain regions, the team found. The research may help explain why some mutations linked to autism affect certain people more strongly than they do others: The mutation’s effect may depend on which parent it came from.

The research may help explain why some 
mutations linked to autism affect certain 
people more strongly than they do others.

A light switch

Changing the balance of excitation and inhibition in neurons instantly reduces social deficits in a mouse model of autism, researchers have found. The finding, by SFARI Investigator Karl Deisseroth and others at Stanford University, implies that the wiring in the brains of these mice is still capable of relatively normal social functioning, and suggests that treatments that change the excitation-inhibition balance might alleviate social difficulties in some individuals with autism.

The researchers, who reported their findings August 2, 2017, in Science Translational Medicine, engineered mice that lack CNTNAP2, a gene linked to autism, and also express special proteins that turn neurons on or off in response to a flash of light.

Mice lacking CNTNAP2 normally show no interest in interacting with unfamiliar mice. But when the researchers exposed these mice to a flash of blue light that caused inhibitory neurons in the prefrontal cortex to fire, the mice became interested in strange mice placed in their cage; the same thing happened when the team used flashes of light to turn off excitatory neurons. The flashes of light also make the mice less hyperactive, the team found. These results boost the long-held theory that over-excitement in the brain is responsible for many autism symptoms.

Sex differences in learning

Male mice with an autism-related mutation struggle with learning tasks that females with the mutation can perform as well as controls, a new study has found. The work, led by SFARI Investigator Ted Abel of the University of Iowa, illuminates some of the mechanisms that appear to protect girls from autism. Autism is almost five times more common in boys than in girls.

The mice in the new study, which was published October 17, 2017, in Molecular Psychiatry, lacked a stretch of DNA called 16p11.2. About 30 percent of people with a deletion in 16p11.2 have autism, and mice with the deletion have cognitive deficits and are hyperactive.

Male mice with the deletion take about three times as long as females with the deletion and controls to learn to poke their noses into a hole for a reward. Males with the deletion also show less perseverance than other mice when the task gets harder.

Abel and his colleagues examined the striatum — one of the brain’s reward centers — in the mice and found that compared with controls and female mice with a 16p11.2 deletion, male mice with the deletion have increased activity in a signaling pathway that dampens neuronal activity, and also increased expression of a dopamine receptor that inhibits learning. Abel is planning further work to drill down into the molecular mechanisms underlying this vulnerability in males and resilience in females.

Antibiotic for autism?

Maternal exposure to infection during pregnancy raises the risk that the baby will have an autism-related condition, according to epidemiological studies. And mice exposed to a maternal infection in utero have a higher risk of autism-like behaviors. But pre-treating pregnant mice with an antibiotic protects their pups from developing these behaviors after a maternal viral infection, even though antibiotics don’t kill viruses, researchers reported in the September 28, 2017, issue of Nature. The study was led by SFARI Investigators Jun Huh of Harvard University, Dan Littman of New York University and Gloria Choi of the Massachusetts Institute of Technology.

The study suggests that infection-induced autism-like features stem from inflammatory immune responses produced by maternal gut bacteria. Previous studies by several of the investigators who worked on the Nature paper showed that in pregnant mice with a viral infection, inflammatory molecules made by ‘T helper 17’ immune cells contribute to the development of cortical abnormalities, social deficits and repetitive behaviors in the mice’s pups.

In the new study, the researchers gave pregnant mice vancomycin, an antibiotic that kills the gut bacteria that spur the growth of T helper 17 cells. Even though the mice were exposed to a virus after antibiotic treatment, their pups developed normally, the researchers found.

Certain bacteria in human intestines also promote the growth of T helper 17 cells. Mice colonized with these bacteria and then infected with a virus gave birth to pups with autism-like features, the researchers found, unless the mothers were pre-treated with an antibody that blocks an inflammatory molecule the T helper 17 cells produce. The researchers hypothesize that women whose gut microbial community is skewed toward the bacteria that generate T helper 17 cells may be more likely than other women to have children with autism if they get an infection during pregnancy.

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