Mutant mice show key autism traits

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Mutant mice show key autism traits

http://www.eurekalert.org/pub_releases/2006-05/cp-mms042706.php

Public release date: 3-May-2006

Contact: Heidi Hardman

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617-397-2879

Cell Press

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, 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 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, W. Luikart, Craig M.

, Jing Zhou, Sharon A. Matheny, Wei Zhang, Yanjiao Li, and

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., 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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