Engineering autism: Mice with extra chromosome region show many autistic signs

June 25, 2009

Mice who inherit a particular chromosomal duplication from their fathers show many behaviors associated with human autism, researchers report in the June 26th issue of the journal Cell, a Cell Press Publication. The duplicated chromosomal region in mice is the equivalent of human chromosome 15q11-13, the most frequent cytogenetic abnormality observed in autism, accounting for some five percent of all cases.

The engineered mice validate the human chromosome abnormality as one cause of the disease, the researchers said. They will also serve as an invaluable tool for therapeutic development.

"We know several mice as 'putative' models of autism, which show face validity that they are similar to human patients," said Toru Takumi of Hiroshima University in Japan. "In addition to these similar phenotypes, our mice have construct validity," meaning that their symptoms are traced to the same biological cause.

Autism is a common and heterogeneous neuropsychiatric disorder with manifestations of impaired social interaction and communication as well as repetitive behavior or restricted interest, the researchers explained. It is also one of the most heritable of all mental disorders, suggesting that genetic factors play an important role in development of the disease.

Scientists have studied many gene candidates, and mice carrying some of those mutations do show some signs. Still the molecular pathways underlying autism remain largely mysterious.

Chromosomal abnormalities are thought to account for 10 to 20 percent of cases and duplication of chromosome 15q11-13 is the only recurrent aberration so far linked to the disease.

In the new study, Takumi's team generated mice with a duplication of a region on their chromosome 7, mirroring the autism-linked abnormality seen in humans. Mice who inherit that abnormality from their fathers show poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations and indications of anxiety, the results of extensive behavioral testing now show.

For instance, when given the option of spending time alone or in the presence of a stranger mouse, normal mice will often choose to hang out with the stranger, Takumi said. Mice with the chromosomal abnormality, on the other hand, more often choose to spend time with inanimate objects over fellow mice.

In tests of spatial memory, in which mice are trained to swim to a hidden platform, animals with the paternally inherited duplication were less able to adapt to changes in the platform's location than normal mice were. Another test, in which mice have to locate the correct hole to exit a box, showed similar results.

"We were honestly surprised to see behavioral inflexibility in two different reversal tests of learning and two different backgrounds," Takumi said. "Higher ultrasonic calls from pups with paternal duplication were unexpected" too. It's also hard to say exactly what those unusual calls mean for the mice, given scientists' limited understanding of mouse communication.

In other tests, the mice showed more signs of fear or anxiety, a feature common in autistic individuals.

The researchers also found molecular-level evidence that the duplication can lead to changes in a receptor for serotonin, a nerve messenger that acts as a growth factor in the immature brain. Those changes stem from different levels of one brain-specific small nucleolar RNA (snoRNA), known as MBII52, a molecule that is known to be involved in physiologically important "edits" to the receptor.

Because the gene that encodes MBII52 is "maternally imprinted," its expression in mice with the inherited duplication from their father was double that of normal mice or those who inherited the same abnormality from their mothers, they report. (Imprinted genes are chemically modified to prevent their expression.) Studies in cultured neurons showed that those changes to MBII52 are associated with an altered neural response, suggesting that changes in serotonin signals might underlie the aberrant behaviors exhibited by the animals.

In addition to those insights, the mice may yet hold many more clues for understanding autism and potential for new treatments.

"The link between social behaviors in rodents and social behavior in humans is difficult to establish," the researchers concluded. "Our model mouse will be valuable not only for therapeutic studies but also provides a starting point for more detailed genetic analysis directed toward understanding the etiology of developmental brain disorders."
-end-
The researchers include Jin Nakatani, Osaka Bioscience Institute, Suita, Osaka, Japan; Kota Tamada, Osaka Bioscience Institute, Suita, Osaka, Japan, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan; Fumiyuki Hatanaka, Osaka Bioscience Institute, Suita, Osaka, Japan, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan; Satoko Ise, Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan; Hisashi Ohta, Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan; Kiyoshi Inoue, Osaka Bioscience Institute, Suita, Osaka, Japan; Shozo Tomonaga, Osaka Bioscience Institute, Suita, Osaka, Japan; Yasuhito Watanabe, Osaka Bioscience Institute, Suita, Osaka, Japan, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan; Yeun Jun Chung, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Ruby Banerjee, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Kazuya Iwamoto, Brain Science Institute, RIKEN, Wako, Saitama, Japan; Tadafumi Kato, Brain Science Institute, RIKEN, Wako, Saitama, Japan, Hiroshima University, Minami, Hiroshima, Japan; Makoto Okazawa, Osaka Bioscience Institute, Suita, Osaka, Japan; Kenta Yamauchi, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan; Koichi Tanda, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan; Keizo Takao, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan, Fujita Health University, Toyoake, Aichi, Japan; Tsuyoshi Miyakawa, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan, Fujita Health University, Toyoake, Aichi, Japan; Allan Bradley, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; and Toru Takumi, Osaka Bioscience Institute, Suita, Osaka, Japan, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan, Hiroshima University, Minami, Hiroshima, Japan.

Cell Press

Related Autism Articles from Brightsurf:

Autism-cholesterol link
Study identifies genetic link between cholesterol alterations and autism.

National Autism Indicators Report: the connection between autism and financial hardship
A.J. Drexel Autism Institute released the 2020 National Autism Indicators Report highlighting the financial challenges facing households of children with autism spectrum disorder (ASD), including higher levels of poverty, material hardship and medical expenses.

Autism risk estimated at 3 to 5% for children whose parents have a sibling with autism
Roughly 3 to 5% of children with an aunt or uncle with autism spectrum disorder (ASD) can also be expected to have ASD, compared to about 1.5% of children in the general population, according to a study funded by the National Institutes of Health.

Adulthood with autism
The independence that comes with growing up can be scary for any teenager, but for young adults with autism spectrum disorder and their caregivers, the transition from adolescence to adulthood can seem particularly daunting.

Brain protein mutation from child with autism causes autism-like behavioral change in mice
A de novo gene mutation that encodes a brain protein in a child with autism has been placed into the brains of mice.

Autism and theory of mind
Theory of mind, or the ability to represent other people's minds as distinct from one's own, can be difficult for people with autism.

Potential biomarker for autism
A study of young children with autism spectrum disorder published in JNeurosci reveals altered brain waves compared to typically developing children during a motor control task.

Autism often associated with multiple new mutations
Most autism cases are in families with no previous history of the disorder.

State laws requiring autism coverage by private insurers led to increases in autism care
A new study led by researchers at the Johns Hopkins Bloomberg School of Public Health has found that the enactment of state laws mandating coverage of autism spectrum disorder (ASD) was followed by sizable increases in insurer-covered ASD care and associated spending.

Autism's gender patterns
Having one child with autism is a well-known risk factor for having another one with the same disorder, but whether and how a sibling's gender influences this risk has remained largely unknown.

Read More: Autism News and Autism Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.