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
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