Mutant Mice Show Key Autism Traits

Science Daily — 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 4, 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."

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 4, 2006. DOI 10.1016/j.neuron.2006.03.023 www.neuron.org

Vulnerability To Measles Among Nursery School Children Risen Sharply

Science Daily — Vulnerability to measles infection has risen sharply among nursery school children in Scotland since 1998, despite recent increases in MMR uptake, reveals research published ahead of print in the Archives of Disease in Childhood.

There are now 25 postcode districts. where more than one in five nursery school children is potentially at risk of catching measles, compared with just three in 1998, when unfounded claims that the vaccine might be linked to autism provoked widespread alarm.

MMR was introduced across the UK in 1988. The recommended schedule is for the first dose to be given at the age of 13 months, with the second dose at between 3 years and 5 years of age.

The researchers looked at the vaccination records for Scotland for all children born between 1987 and 2004, accounting for over one million children.

The records show that the sharpest decline began for children born from 1999 onwards, rather than for those born in 1997 as might be expected. This suggests that the negative publicity had a gradual but cumulative effect, say the authors.

The most affluent sectors of the population tended to either have their children vaccinated early or not at all, the figures show. But parents in the most deprived areas of Scotland tended to delay vaccinating their children.

The increased risks of measles to nursery school children are concerning, particularly in the areas of greatest deprivation, where the risk of measles outbreaks would add to existing health inequalities, say the authors.

Although rates of MMR vaccine uptake have increased across Scotland, these have not yet reached the levels before 1998, and are not expected to reach the levels required for population protection among young schoolchildren, say the authors.

Note: This story has been adapted from a news release issued by BMJ Specialty Journals.

The Role Of Evolutionary Genomics In The Development Of Autism

Science Daily — Scientists at the London School of Economics, UK and Simon Fraser University, Canada have described the first hypothesis grounded in evolutionary genomics explaining the development of autism.

In an article to be published in a forthcoming issue of Journal of Evolutionary Biology, Dr Christopher Badcock and Professor Bernard Crespi explore the 'imprinted brain hypothesis' to explain the cause and effect of autism and autistic syndromes such as Asperger's syndrome, highlighted by the book The Curious Incident of the Dog in the Night-Time, which involves selective disruption of social behaviour that makes individuals more self-focussed whilst enhancing skills related to mechanistic cognition.

The 'imprinted brain hypothesis' suggests that competition between maternally and paternally expressed genes leads to conflicts within the autistic individual which could result in an imbalance in the brain's development. This is supported by the fact that there is known to be a strong genomic imprinting component to the genetic and developmental mechanisms of autism and autistic syndromes.

Professor Bernard Crespi from Simon Fraser University, Canada explains: "The imprinted brain hypothesis underscores the viewpoint that the autism spectrum represents human cognitive diversity rather than simply disorder or disability. Indeed, individuals at the highest-functioning end of this spectrum may have driven the development of science, engineering and the arts through mechanistic brilliance coupled with perseverant obsession."

The core behavioural features of autism such as self-focussed behaviour, altered social interactions and language and enhanced spatial and mechanistic cognition and abilities -- as well as the degree to which the brain functions and structures are altered -- also supports this hypothesis.

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Read or download the article for FREE: http://www.blackwell-synergy.com/doi/full/10.1111/j.1420-9101.2006.01091.x.

Note: This story has been adapted from a news release issued by Blackwell Publishing Ltd.