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A 'three-hit' theory of autism

Since the first case was documented in the United States in 1938, finding causes for autism have remained elusive. Hundreds of genes and environmental exposures have been implicated. But, 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 fact caught the attention of Rockefeller University's Donald W. Pfaff PhD, a neurobiologist studying hormone effects and sex differences in the brain. Pfaff wondered if being male might somehow amplify genetic and environmental risk factors for autism.

Collaborating with colleagues specializing in child neurology and psychology, he proposes a "three-hit" theory of autism. It suggests (1) a genetic predisposition, combined with (2) early stress is more detrimental to (3) boys than to girls — and more likely to produce social avoidance, a hallmark of autism disorders. His lab has now found evidence in mice supporting his 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 three individually."

Donald W. Pfaff PhD, Professor and Head, Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, New York, USA. Member in the David Rockefeller Graduate Program and the Tri-Institutional MD - PhD Program.


Pfaff formed the three-hit theory based on animal studies suggesting the male hormone testosterone may sensitize a developing brain to stress, which leads to social avoidance, a characteristic of autism. Mice like humans, are social animals.

In experiments, Pfaff's team observed male mice to see if they were more prone to problems with social responses than females when the two other risk factors were also present. The theory and the experiments focused on the primary aspect of autism spectrum disorders, problems in social interaction. Autism is also associated with difficulties in communication and restricted intellectual interests.

Results are published in the Proceedings of the National Academy of Sciences (PNAS).

To achieve a gene hit, Sara Schaafsma, postdoc, led a team in observing pregnant mice lacking a gene frequently found mutated in people diagnosed with autism. To evoke stress in their unborn pups, her team introduced bacterial infection into the pregnant moms, prompting an immune response. After the pups matured, they tested their social behavior in a series of experiments.


The most compelling evidence for the three-hit theory came in social recognition. Most mice, even with (1) genetic risk and (2) stressed from intra-uterine bacterial infection, recognize a new mouse after multiple meetings. But mice with all three hits of (1) genetically predisposed to autism, (2) stressed by intra-uterine bacterial infection, and (3) male — were unable to recognize new mice after multiple encounters.


Researchers next looked for molecular changes within these rodents' brains that might explain their differences in behavior. In a brain region called the left hippocampus, they found increases in gene function that trigger stress response. The C. David Allis lab then collaborated looking for chemical alterations in how DNA is packaged (folded) that might explain the increase. This revealed one chemical change within the nerve cell nucleus which amplifies function of a stress-relevant gene.


"Neurodevelopmental disorders, including autism, are often attributed to an interaction between genetic — 'nature' — and environment — 'nurture.'

Our work indicates how male sex comes to be an important component of this dynamic, at least for one major aspect of autism.

By collecting a variety of evidence, we have begun to uncover one molecular mechanism, of many, by which these three hits alter sociability."

Donald W. Pfaff PhD


Significance
Autism spectrum disorders (ASDs) comprise a heterogeneous set of neurodevelopmental disorders. Although hundreds of genes have now been identified to be associated with ASD, genetic factors cannot fully explain ASD’s incidence. The early environment is now known to be pivotal in ASD’s etiology too. In the face of this complexity, one aspect of ASD has stood out constantly as a causative biological factor: the sex difference. Approximately 80% of the children diagnosed are boys. This current set of experiments tests, in an animal model, the “three-hit theory of autism,” which states that interactions among (i) being male, (ii) suffering early (especially, prenatal/immunological) stress, and (iii) having certain genetic mutations will predispose to an ASD diagnosis.

Abstract
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.

Key Words: maternal immune activation prenatal stress sex differences Cntnap2 autism

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Understanding sex bias in autism spectrum disorder
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Mar 24, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   



In the male mouse left hippocampus, increases in gene function were found that trigger stress responses.
One chemical change within the nerve cell nucleus amplifies the stress-relevant gene.
Image Credit: Nature Reviews

 


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