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New Findings Help Pinpoint Autism's Genetic Roots
Main Category: Autism News
Article Date: 08 May 2006 - 9:00am (PDT)

By deleting a gene in certain parts of the brain, researchers at UT Southwestern Medical Center have created mice that show deficits in social interaction that are reminiscent of humans with autism spectrum disorders.

The investigators also found physical abnormalities in the brains that mimic some cases of autism, showing that the research animals can be useful in studying the mysterious condition.

The finding - to be published in the May issue of the journal Neuron - confirms recent indications that a mutation in this particular gene could cause at least some forms of autism, said Dr. Luis F. Parada, director of the Center for Developmental Biology and the study's senior author. Dr. Parada also directs the Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration.

"The exciting thing about this mouse is it helps us to zero in on at least one anatomic location of abnormality, because we targeted the gene to very circumscribed regions of the brain," he said. "In diseases where virtually nothing is known, any inroad that gets into at least the right cell or the right biochemical pathway is very important."

Autism is a brain disorder in which people have trouble with communication and social interaction and engage in repetitive movements. Usually manifesting in childhood, it affects about one in every 250 people, primarily males.

The researchers focused on a gene called Pten, which is also known to suppress cancers in humans. Some people with autism have mutations in Pten, but it has been unclear if that's what causes the disease, Dr. Parada said. To test that hypothesis, the researchers deleted the gene in the front of the mouse brain and in areas of the hippocampus, a structure involved in memory and other functions.

Mice, which are social animals, are a good model for studying the disease, Dr. Parada said. Their behavior can be studied when they are exposed to other mice, when they are provided with inanimate objects and material for making nests, and when they are placed in unfamiliar environments.

In each of those conditions, the mutant mice were distinctly different from normal mice that came from the same litter.

Mice lacking the Pten gene were generally uninterested in unfamiliar mice, while normal mice approached the strangers. When mutant mice were exposed to both an inanimate object and another mouse, they showed about equal interest in each - echoing the way children with autism prefer toys to people - while the normal mice preferred the other mouse.

When given raw material for nesting, the mutants ignored it, while the normal mice teamed up to build nests. And the pups of mutant females often died from lack of maternal care.

The genetically altered mice were also hypersensitive to stressful stimuli, such as being picked up, being subjected to a sudden noise, or being put in a lighted or open area. People with autism are similarly overly sensitive to sensory stimuli.

The mutant mice's brains were also noticeably altered in the areas where the gene was deleted. The nerve cells were thicker than normal and had a higher-than-normal number of connections to other nerve cells. This may lead to the sensory overload that people with autism experience, Dr. Parada said.

"It would be really exciting if it turned out that we've zeroed in on the anatomical regions where things go wrong in autistic patients, regardless of how the autism occurs," he said, adding that the next step in the research is to treat the mice with drugs to see whether it's possible to reverse the condition.

Autism-like syndromes are being studied at UT Southwestern from another angle through the work of Dr. Lisa Monteggia, assistant professor of psychiatry.

Her investigation of the role of a gene called MeCP2 in mediating autistic-like behavior has been published recently in the journals Biological Psychiatry and Current Biology. Mutations in MeCP2 occur in a pervasive developmental disorder called Rett syndrome, a human disease that shares many clinical features with autism. Mutations in MeCP2 also have been identified in autism patients.

In Biological Psychiatry, she described how the selective deletion of MeCP2 in the brains of mice - in similar areas as those targeted by Dr. Parada - creates many of the features of Rett syndrome that are also observed in autism patients, including reduced social interaction, abnormal repetitive behavior and increased anxiety.

Current Biology reported her collaborative study with Dr. Ege Kavalali, associate professor in the Center for Basic Neuroscience, in which recorded signals from nerve cells in the mouse brain showed that in those lacking MeCP2, there was an imbalance between signals that excite nerve cells and those that inhibit neural activity. Such an imbalance in nerve transmission has been hypothesized as a feature of human autistic disorders; however, this is the first report demonstrating such an imbalance.

Lead authors in the Pten study from the Center for Developmental Biology were Dr. Chang-Hyuk Kwon, postdoctoral researcher; former graduate student Bryan Luikart, now at Oregon Health & Science University; and Dr. Craig Powell, assistant professor of neurology and psychiatry at UT Southwestern. The work was supported by the American and Lebanese Associated Charities, the National Institutes of Health and the American Cancer Society.

UT Southwestern scientists participating in the MeCP2 research were Erika Nelson, student research assistant in psychiatry, and Terry Gemelli, former research associate in psychiatry.

Dr. Monteggia's research is supported in part by the National Alliance for Autism Research, Once Upon A Time …, and the Rett Syndrome Research Foundation.

Mutant Mice Show Key Autism Traits
Main Category: Autism News
Article Date: 07 May 2006 - 20:00pm (PDT)

While the causes of autism remain complex and mysterious, researchers are steadily adding pieces to its intricate puzzle. In what they believe to be a significant new approach to understanding "autism spectrum disorders" (ASD), researchers have developed a mouse that shows abnormal social interactions and brain hypertrophy characteristic of the disease.

In an article in the May 2006, Neuron, Luis Parada and his colleagues report the results of removing (knocking out) a single gene associated with brain disorders in mice. The gene, called Pten, had been associated with a broad array of such disorders when knocked out throughout the animals' bodies. However, Parada and colleagues engineered mice to knock out the gene only in mature, or "postmitotic," neurons of the cerebral cortex and hippocampus in the brain. These regions are associated with higher brain function such as learning and memory.

The mutant mice showed major abnormalities in a variety of social interactions normally undertaken in mice, found the researchers. For example, they were far less likely to approach and sniff new mice introduced into their cage, compared to normal mice. And while normal mice show markedly less interest when such new mice are later reintroduced, the mutant mice did not show such a reduction in interest. This abnormality indicated "impaired social learning or inability to identify the juvenile due to the low level of initial interaction," wrote the researchers.

In other tests of social behavior, the researchers found that--when given the choice of investigating a cage holding another mouse or an empty cage--the mutant mice showed similar preference for the two. Normal mice by far prefer investigating the caged mouse.

The researchers also found the mutant mice to be deficient in nest-forming and sexual and maternal behavior. In tests of their reaction to such sensory stimuli as bright environments, the mutant mice showed hyperactivity and increased anxiety. They also showed sporadic seizures.

The researchers concluded that "the mutant mice exhibited deficits in all social paradigms tested and also showed exaggerated reaction to sensory stimuli, anxiety-like behaviors, seizures, and decreased learning, which are features associated with ASD."

Finally, the researchers found that the mutant mice showed the same kind of abnormal overgrowth of neurons and their interconnections seen in some people with ASD that also show increased brain volume and enlarged heads.

Wrote Joy Greer and Anthony Wynshaw-Boris in a preview in the same issue of Neuron, "caution is warranted because there are aspects of ASD that are not recapitulated in the Pten mutants. For example, the Pten mutants do not display the expression of abnormal repetitive behaviors seen in ASD, although it is unreasonable to expect perfect phenotypic overlap of human ASD with any mouse model."

Also, they wrote, "as appropriately pointed out by the authors, Pten deletion is restricted to postmitotic neurons in the CNS [central nervous system] in their model, and current evidence suggests that ASD is a developmental rather than a neurodegenerative disorder."

Greer and Wynshaw-Boris concluded that "Whether or not the findings . . . have direct relevance to ASD, the experimental results described are intriguing and represent an important entry point to understanding the role of Pten in postmitotic neurons of the hippocampus and cortex as well as providing new insight into the molecular correlates mediating social- and anxiety-related behaviors in the postnatal CNS."

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The researchers include Chang-Hyuk Kwon, Bryan W. Luikart, Craig M. Powell, Jing Zhou, Sharon A. Matheny, Wei Zhang, Yanjiao Li, and Luis F. Parada of the University of Texas Southwestern Medical Center in Dallas, TX; Suzanne J. Baker of St. Jude Children's Research Hospital in Memphis, TN. This work was supported in part by the American and Lebanese Associated Charities, NIH grant NS44172 (to S.J.B), and NIH grant R37NS33199 and the American Cancer Society (to L.F.P.).

Kwon et al.: "Pten Regulates Neuronal Arborization and Social Interaction in Mice." Publishing in Neuron, 50, 377–388, May 2006. DOI 10.1016/j.neuron.2006.03.023 whttp://www.neuron.org/

Autism Has High Costs To US Society
Main Category: Autism News
Article Date: 27 Apr 2006 - 18:00pm (PDT)

It can cost about $3.2 million to take care of an autistic person over his or her lifetime. Caring for all people with autism over their lifetimes costs an estimated $35 billion per year. Those figures are part of the findings in the first study to comprehensively survey and document the costs of autism to U.S. society. Michael Ganz, Assistant Professor of Society, Human Development, and Health at Harvard School of Public Health, authored the study, which appears in a chapter titled, "The Costs of Autism," in the newly published book, Understanding Autism: From Basic Neuroscience to Treatment (CRC Press, 2006). Ganz hopes his research will help policymakers allocate scarce resources to its treatment and prevention as well as provide a useful reference for policymakers and advocates to help them more fully understand the financial impact of autism on U.S. society.

Ganz's analysis of the costs includes direct and indirect medical costs associated with the disorder. But he believes the $35 billion annual societal cost for caring for and treating people with autism likely underestimates the true costs because there are a number of other services that are used to support individuals with autism, such as alternative therapies and other family out-of-pocket expenses, that are difficult to measure. In addition, Ganz believes that the level of cost could be higher if there were more useful and widespread treatment options available. "Given that the federal autism research budget has been historically less than $100 million per year and given that research budgets for other conditions with similar numbers of affected individuals are sometimes orders of magnitude higher, I hope that my research can help focus more attention on directing more resources toward finding prevention and treatment options for autism," Ganz said. (For comparison purposes, he notes estimated annual costs of other conditions, including Alzheimer's disease ($91 billion); mental retardation ($51 billion); anxiety ($47 billion); and schizophrenia ($33 billion).)

Autism is a pervasive developmental disorder (PDD) that involves severe deficits in a person's ability to communicate and interact with others. Children with autism often have trouble using their imagination, have a limited range of interests, and may show repetitive patterns of behavior or body movements. The disorder is often associated with some degree of mental retardation. Autism is the most prevalent PDD and the most common of all serious childhood disorders. It affects an estimated 1.5 million Americans and is increasing at a rate of 10-17 percent each year. It is four times more common in boys than in girls. The exact cause of autism is not known and there is currently no cure for the disorder.

Ganz broke down the total costs of autism into two components: direct and indirect costs. Direct costs include direct medical costs, such as physician and outpatient services, prescription medication, and behavioral therapies (estimated to cost, on average, more than $29,000 per person per year) and direct non-medical costs, such as special education, camps, and child care (estimated to annually cost more than $38,000 for those with lower levels of disability and more than $43,000 for those with higher levels).

Indirect costs equal the value of lost productivity resulting from a person having autism, for example, the difference in potential income between someone with autism and someone without. It also captures the value of lost productivity for an autistic person's parents. Examples include loss of income due to reduced work hours or not working altogether. Ganz estimates that annual indirect costs for autistic individuals and their parents range from more than $39,000 to nearly $130,000.

Since people with autism receive services from a wide variety of sources, Ganz believes future research efforts should focus on identifying those sources and linking those costs to non-financial data about the burdens of autism. These complementary sources of data can provide a richer picture that will be useful to policymakers in the future to assist them in devoting resources to address the financial and non-financial effects of autism.