Autism Bias toward Males Explained through Signaling Pathway

Neurodevelopmental disorders, including autism spectrum disorders (ASD), are highly male biased, but the underpinnings of this are unknown. Striatal dysfunction has been strongly implicated in the pathophysiology of neurodevelopmental disorders, raising the question of whether there are sex differences in how the striatum is impacted by genetic risk factors linked to neurodevelopmental disorders.

Now, new research by investigators at the University of Iowa Carver College of Medicine and University of Pennsylvania – aiming to understand why ASD is more common in boys – has uncovered differences in a brain signaling pathway involved in reward learning and motivation that make male mice more vulnerable to an autism-causing genetic glitch.

Nearly one in every 200 cases of autism is caused by the deletion of a section of DNA on chromosome 16 – a molecular defect also known as a copy number variation (CNV). The mouse model used in the current study and by other ASD researchers is missing the same stretch of DNA. The researchers tested the mice for abnormalities in reward-learning behavior – learning to associate actions with rewarding outcomes. This type of learning is mediated by a part of the brain called the striatum and is disrupted in people with autism and other neurodevelopmental disorders.

Findings from the new study, published in Molecular Psychiatry in an article entitled “Male-Specific Deficits in Natural Reward Learning in a Mouse Model of Neurodevelopmental Disorders”, showed that only male mice with the autism-associated genetic deletion have abnormal reward-learning behavior.

“One intriguing aspect of autism is that it predominantly affects males; four boys are affected for every one girl,” explained senior study investigator Ted Abel, Ph.D., director of the Iowa Neuroscience Institute at the University of Iowa Carver College of Medicine. “We don’t understand what it is about this disorder that predisposes boys as compared to girls to develop autism.”

Interestingly, female mice with the same genetic deletion are not affected. Moreover, these sex-specific behavioral differences are accompanied by sex differences in molecular signaling pathways in the striatum brain region.

“Problems with reward learning could explain why individuals with autism don’t interact socially – because they don’t find it is rewarding in the same way,” Dr. Abel remarked. “It could explain why people with autism have restricted interests – because they find only very selective things rewarding – and it could explain the differences in language acquisition – because the neural circuitry involved in reward learning is the same circuitry that mediates both language learning and production.”

One of the genes contained in the missing section of DNA is an important signaling protein called ERK1, or extracellular-signal related kinase 1. The activity of this protein affects the function of the striatum—the part of the brain that’s involved in reward learning and motivation. In the current study, the researchers found that male mice carrying this genetic deletion have increased activation of ERK1 in the striatum coupled with decreased amounts of another protein that reduces ERK1 activity. In contrast, the female mice carrying the genetic deletion do not have overactivated ERK1. Also, despite the genetic deletion, the female deletion mice have higher levels of ERK1 than the male deletion mice. All of these molecular differences mean that ERK1 signaling is particularly sensitive to disruption in male mice.

“This is some of the first evidence in a mouse model of autism of a ‘female protective effect,’ from the behavioral to the molecular level,” noted lead study investigator Nicola Grissom, Ph.D., assistant professor of psychology at the University of Minnesota. “These findings shed valuable new light on the science of neurodevelopmental disorders, many of which are more common in boys. However, they also address the broader question of how sex and gender influence the neurobiology of how we learn and behave, which may be involved in the different levels of risk between women and men in developing many other neuropsychiatric conditions, as well.”

The research team also found that male mice carrying this genetic alteration linked to autism have increased expression of a receptor for dopamine—the D2 receptor. The level of D2 expression did not increase in the female autism mice. The authors noted that risperidone, one of the few drugs that is approved by the FDA to treat ASD symptoms, targets D2 dopamine receptors.

All of these new findings are part of a bigger study where Dr. Abel and his colleagues are investigating many different mouse models of autism, in which different autism-linked genes have been disrupted. The researchers are seeking commonalities among the different models. One emerging theme, supported by the new study, is that a deficit in reward learning may be a common feature of ASD, and males are specifically deficient in this type of behavior.

“We think we are on the right track,” Dr. Abel commented. “We have begun to identify what may be an underlying reason why neurodevelopmental disorders predominantly affect boys, and that involves the function of the striatum and reward learning. This has implications for how we think about the underlying behavioral differences in autism and implications for how we develop both behavioral or pharmacological therapies to improve the lives of those with autism.”