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Study Tests ‘Three Hit’ Theory of Autism

Summary: A new study reports a genetic predisposition in combination with early life stress appear to be more detrimental to males over females and may produce the social avoidance often associated with autism spectrum disorders.

Source: Rockefeller University.

Since the first case was documented in the United States in 1938, the causes of autism have remained elusive. Hundreds of genes, as well as environmental exposures, have been implicated in these brain disorders. Sex also seems to have something to do with it: About 80 percent of children diagnosed with an autism spectrum disorder are boys.

This striking bias caught the attention of Rockefeller University’s Donald W. Pfaff. A neurobiologist who studies hormone effects and sex differences in the brain, Pfaff wondered if maleness might somehow amplify the genetic and environmental risk factors for the disease.

In collaboration with colleagues specializing in child neurology and psychology, he has proposed a “three-hit” theory of autism, which suggests that a genetic predisposition in combination with early stress is more detrimental to boys than to girls, and more likely to produce the social avoidance that is a hallmark of autism disorders. Now, a team in his lab has found evidence in mice supporting this theory.

“Together, these three hits–genes, environment, and sex–build on one another, such that their combined effect on behavior is much greater than the sum of the three individually,” says Pfaff, head of the Laboratory of Neurobiology and Behavior.

A test run

Pfaff and his colleagues formulated the three-hit theory based on studies of animals suggesting that the male hormone testosterone may sensitize the developing brain to stress in a way that can lead to social avoidance, a behavior characteristic of autism. Mice, like humans, are social animals, and in experiments, described in the Proceedings of the National Academy of Sciences, Pfaff’s team looked to see if male mice were more prone to problems with social responses than females when the other two risk factors were present.

The theory and these experiments focus on the primary aspect of autism spectrum disorders, social problems, but there are others. In addition to social avoidance, autism is associated with difficulties in communication, as well as unusually restricted interests.

Image shows a blackboard with the word "autism" written on it.

The theory and these experiments focus on the primary aspect of autism spectrum disorders, social problems, but there are others. In addition to social avoidance, autism is associated with difficulties in communication, as well as unusually restricted interests. NeuroscienceNews.com image is for illustrative purposes only.

To achieve a genetic hit, the team, led by Sara Schaafsma, a postdoc in the lab, used mice lacking a gene that is frequently mutated in people diagnosed with autism. To evoke stress in the as-yet unborn mice, the researchers prompted the immune systems of their pregnant mothers to react as though under attack from bacteria.

Changes in brain and behavior

The researchers later tested the social behavior of these mice in a series of experiments. The most compelling evidence for the three-hit theory came from a test of social recognition. Most of the animals, even those with two risk factors, showed signs of recognizing a once-unfamiliar mouse over multiple encounters. Only mice with all three hits–those that were male, were genetically predisposed to autism, and had experienced stress as embryos–seemed unable to recognize new acquaintances after encountering them multiple times.

Next, the researchers looked for molecular changes within these rodents’ brains that might help to explain the differences in behavior. They found an increase in the expression of a gene that helps to kick off stress responses, in a brain region called the left hippocampus. With help from C. David Allis’s lab, they looked for chemical alterations in the packaging of DNA that might explain this uptick in gene activity. This effort revealed one particular chemical change in the nerve cell nucleus that encourages the expression of this stress-relevant gene.

“Neurodevelopmental disorders, including autism, are often attributed to an interaction between genetic ‘nature’ and environmental ‘nurture.’ Our work indicates how male sex comes to be an important component of this dynamic, at least for one major aspect of autism,” Pfaff says. “By collecting a variety of evidence, we have begun to uncover one molecular mechanism, of many, by which these three hits alter sociability.”

About this autism research article

Funding: Autism Science Foundation, Simons Foundation Autism Research Initiative funded this research.

Source: Katherine Fenz – Rockefeller University
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Sex-specific gene–environment interactions underlying ASD-like behaviors” by Sara M. Schaafsma, Khatuna Gagnidze, Anny Reyes, Natalie Norstedt, Karl Månsson, Kerel Francis, and Donald W. Pfaff in PNAS. Published online January 23 2017 doi:10.1073/pnas.1619312114

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Rockefeller University “Study Tests ‘Three Hit’ Theory of Autism.” NeuroscienceNews. NeuroscienceNews, 4 March 2017.
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Rockefeller University (2017, March 4). Study Tests ‘Three Hit’ Theory of Autism. NeuroscienceNew. Retrieved March 4, 2017 from http://neurosciencenews.com/genetics-sex-environment-autism-6210/
Rockefeller University “Study Tests ‘Three Hit’ Theory of Autism.” http://neurosciencenews.com/genetics-sex-environment-autism-6210/ (accessed March 4, 2017).

Abstract

Sex-specific gene–environment interactions underlying ASD-like behaviors

The male bias in the incidence of autism spectrum disorders (ASDs) is one of the most notable characteristics of this group of neurodevelopmental disorders. The etiology of this sex bias is far from known, but pivotal for understanding the etiology of ASDs in general. Here we investigate whether a “three-hit” (genetic load × environmental factor × sex) theory of autism may help explain the male predominance. We found that LPS-induced maternal immune activation caused male-specific deficits in certain social responses in the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD. The three “hits” had cumulative effects on ultrasonic vocalizations at postnatal day 3. Hits synergistically affected social recognition in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior. In brains of the same mice we found a significant three-way interaction on corticotropin-releasing hormone receptor-1 (Crhr1) gene expression, in the left hippocampus specifically, which co-occurred with epigenetic alterations in histone H3 N-terminal lysine 4 trimethylation (H3K4me3) over the Crhr1 promoter. Although it is highly likely that multiple (synergistic) interactions may be at work, change in the expression of genes in the hypothalamic–pituitary–adrenal/stress system (e.g., Crhr1) is one of them. The data provide proof-of-principle that genetic and environmental factors interact to cause sex-specific effects that may help explain the male bias in ASD incidence.

“Sex-specific gene–environment interactions underlying ASD-like behaviors” by Sara M. Schaafsma, Khatuna Gagnidze, Anny Reyes, Natalie Norstedt, Karl Månsson, Kerel Francis, and Donald W. Pfaff in PNAS. Published online January 23 2017 doi:10.1073/pnas.1619312114

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