Singapore, Jun 29, 2009: Mice who inherit a particular chromosomal duplication from their fathers show many behaviors associated with human autism, researchers reported in the June 26th issue of the journal Cell. 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.

"We know several mice as 'putative' models of autism, which show face validity that they are similar to human patients," said Mr 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. 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.

In the new study, Mr 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.

"We were honestly surprised to see behavioral inflexibility in two different reversal tests of learning and two different backgrounds," Mr 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.

According to the researchers, the gene that encodes MBII52 is "maternally imprinted," and because of this 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.

"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."