OSU-CHS translational research team probing autism spectrum disorders

Thursday, February 18, 2010

More than two dozen research professionals at the Oklahoma State University Center for Health Sciences are taking a team approach to examine multiple aspects of autism spectrum disorders (ASD) and how these factors may interact to lead to ASD’s development.

“The individuals involved in this project all bring a high level of passion along with their expertise,” says neuropharmacologist and group spokesperson David Wallace, Ph.D., about the translational research group of behavioral and biomedical scientists, physicians, statisticians and hyperbaric medicine experts.

ASD encompasses autism disorder, or “classic autism,” Asperger syndrome, and Pervasive Developmental Disorder Not Otherwise Specified (or atypical autism). It affects communication and social interaction, and symptoms appear early in life. A single cause is not known and multiple causes are suspected including genetic components, environmental factors or changes in the digestive system.

“This is what used to be called a pervasive development disorder,” said Stanley E. Grogg, D.O., a pediatrician and research group member who also is Interim President and Dean of OSU-CHS and the College of Osteopathic Medicine.  “Evaluations at 18 months and two years of age are standards for diagnosis of ASD, which affects one in every 150 children in the U.S.”

The project, still in its early stages, took root at last year’s OSU-CHS Research Day, when Tom Curtis, Ph.D., a physiologist who researches dopamine and pair-bonding in prairie voles, saw a poster by Wallace and OSU-CHS graduate student, Amber Hood, M.S., that examined the toxic effects of heavy metals on dopamine systems in the brain.

“When voles pair-bond it changes the brain, and when dopamine is released it causes them to be anti–social toward unfamiliar animals,” Curtis explained, saying the behavior resembles the aversive response some autistic people have toward strangers.

Curtis reasoned that if heavy metals alter dopamine, they also might affect social behavior in voles, perhaps causing behavioral changes resembling autism. His findings show male voles that were exposed to mercury showed significant reductions in social function. Voles who were not exposed spent most of their time cuddling, their usual behavior.  “And here’s where it gets really interesting; it only happened in the males,” Curtis said. “Female voles who were exposed were indistinguishable from ones who didn’t. This provides an interesting parallel to humans; ASD occurs most often in boys.”

Curtis says just making this behavior happen is intriguing, but that getting parallel changes in the brain that are consistent with behavior change is what ties it all together. Repeating the tests with other metals will add to the data. “If our hypothesis is right, we should see similar effects,” Curtis said.

Causes of autism may be complex, but knowledge is growing. “One thing we do know is that drugs targeting the human dopamine system can significantly impact autistic behaviors.  No one really knows why, and what we are proposing is a specific target or mechanism by which negative behavior arises and may be affected by the dopamine. We may gain further understanding if other types of exposures produce the same results,” he said.

Adding other heavy metals, commonly thought of to be environmental toxins, combining and layering them to look at different facets and identifying branch points are possible future approaches. Pesticides, food additives, or trying to find drugs that could reverse processes also may be part of future studies. Studying exposure in utero or post partum to try to determine whether estrogen is protecting the females also is a possibility.

Wallace explained that in addition to behavioral studies, researchers are examining changes in the brain and other organ systems to try to correlate to the observed behavioral alterations.

Wallace and pharmacologist Randall Davis, Ph.D., are investigating changes in the brain associated with heavy metal exposure. Wallace’s group is examining dopamine transporter function after heavy metal exposure. The dopamine transporter is a protein responsible for removing dopamine and stopping its action. A change in function in this clearance of dopamine would lead to numerous behavioral changes. Some of the prescription drugs previously used to control the symptoms of ASD function by modulating the dopamine system in the brain.  Emerging evidence from Davis’ team suggests that glial activation and neuroinflammation may be instrumental in the neuropathology of autism.

Wallace and Davis are developing the foundation for the behavioral/neurotoxicity correlations. The role of heavy metals and neuroinflammation is being studied, with an interest in characterizing the modulation of neuroinflammatory pathways in specific brain regions and cell types within the brain following heavy metal exposure. These studies are carried out using both in vivo (vole) and in vitro (human astroglial cells) model systems.

Immunologist Rashmi Kaul, Ph.D., and her lab associates are probing the effects of heavy metals on liver function, Wallace said.  The liver may be playing a secondary role in the development of ASD. This hard-working organ is central for metabolic processes and is involved in manufacturing protein structures for hormones, neurotransmitters and various human protein forms. Its specialized Kupffer cells help with detoxification to maintain liver immune homeostasis and reduce inflammation.

In addition, it is the main organ for detoxifying biotoxins, neurotoxins and heavy metal pollutants that may be transported from the intestines via portal and lymphatic circulation in exposed individuals. It also plays a significant role in immune health. So as heavy metals reduce the ability of the liver to detoxify the body, toxin concentrations will build, leading to changes in brain function.

“We hypothesize that heavy metals in the liver can lead to ineffective function of the liver and various other processes involved.  Right now we are studying the gender-related immune responses and inflammation in the liver in a behavioral vole animal model chronically exposed either to mercury or to various other metals,” Wallace said.

Another area of high interest in the development of ASD is the possibility of changes in gut/intestine function, which may lead to the behavioral changes associated with ASD.  “Impaired gut function may be central to the causes, or a secondary consequence, of these disorders”, Wallace said. He said microbiologist Gerwald Köhler, Ph.D., is using the vole model to investigate the role of the gut microflora in gastrointestinal pathologies observed in some autism spectrum disorders.

Recent research has shown that the numerous microbes forming the normal flora in the mammalian gut are crucial to nutrition, defense against pathogens, gut immune system regulation, and even intestinal development. The researchers are using molecular approaches to characterize the gut microflora in voles and currently are examining changes in its composition resulting from environmental insults such toxic metal exposure.

Correlation of findings with behavioral outcomes and other results from the collaborative research group will help to uncover interactions between gut and brain. Future research will be directed toward explaining of the role of the gut microflora in intestinal development and whether early disturbances in the establishment of a healthy gut flora can lead to gastrointestinal abnormalities, with far reaching consequences for nervous system function.

Anecdotal data suggest that oxygen may help with ASD. The research team is exploring a future option to conduct evidence-based studies to determine the usefulness of hyperbaric treatment or extreme oxygen therapy with children who have been diagnosed with this disorder.

The theory behind this clinical approach is that an oxygen-enriched environment stimulates neuronal development, improving behavioral function.  Wallace said the multidisciplinary team of investigators will balance their scientific skepticism with open-minds when exploring alternative treatments such as the use of hyperbaric medicine, especially since therapies such as this one are widely reported to have positive clinical outcomes for autistic children.  Medical professionals and parents need to understand whether these therapies work, under what circumstances, and why they work. The proposed study would include pre- and post-treatment developmental testing and other evaluations to establish benchmarks, and a final evaluation would conclude the project.

Developing additional experiments and evaluating of the efficacy of treatment are research targets. “We hope we can use voles to develop a model system that is cost-effective, and can repeat combinations that show behavioral changes,” Wallace said about future goals.  “We want to be able to screen a variety of compounds such as pesticides, food additives, and both prescription and illegal drugs that could participate in the development of ASD.  Once we have a better understanding of the causes of the disorder, we will be able to target therapies much better to manage the treatment of ASD.”

Wallace said that a biomedical research building now being constructed on the OSU-CHS campus will provide 78,000 square feet for research and education, allowing researchers participating in the autism project to collaborate in one location.  “It also will attract and permit the hiring of highly qualified researchers who will contribute to the autism team and further advance our understanding of this disorder,” he said.