Mouse model could provide clues to autistic behaviors

- By Alissa Poh

Scientists have developed a new mouse model to help illuminate the vagaries of autism, according to a study from a School of Medicine researcher and other colleagues.

The study focused on mice missing the gabrb3 gene, which codes for a protein important in brain development and normal adult brain function, said David Clark, PhD, associate professor of anesthesiology and the paper's senior author. The study, led by Timothy DeLorey, PhD, a neuroscientist at the Molecular Research Institute in Palo Alto, used mice developed by co-author Gregg Homanics, PhD, professor of anesthesiology and pharmacology at the University of Pittsburgh.

The combined efforts of many in the field of autism research may be starting to pay off, said Clark. The study of the mouse model is published in the March issue of Behavioral Brain Research.

Autism occurs approximately once in every 150 births, with males being four times more likely to develop this disorder. It has many faces, and is often called autism spectrum disorder, or ASD. Asperger's syndrome, for example, lies at the high-functioning end of this spectrum; individuals with this disorder are socially awkward, but can hold jobs and maintain relationships. At the other end are varying degrees of mental retardation, including Fragile-X syndrome, chromosome 15 duplication syndromes and Angelman syndrome, where affected individuals move like marionettes and constantly laugh for no apparent reason.

'We are gaining some traction on very complex diseases like ASD,' said Clark, 'with the application of more sophisticated genetic and behavioral techniques.' While this could lead to better understanding of autism and possible treatment targets, he added that alterations in the function of the gabrb3 gene are unlikely to cause all types of ASD.

The three hallmarks of autism are impaired social skills, repetitive behavior (such as hand-wringing and rocking back and forth) and problems with language and communication. These are readily recognizable in humans, but can we tell, similarly, if a mouse is autistic?

The answer is a qualified yes. The team found that their mouse model displays two of autism's three main traits: social deficiency and repetitive actions. The mice also exhibit other autism-associated characteristics, such as abnormal exploratory behavior, and deficits in nonselective attention, thought to be involved in shifting or orienting attention from one target or place to another.

In this study, the researchers put mice lacking the gabrb3 gene through a series of tests to assess their social and exploratory competence.

First, the researchers placed the mice in a specially designed test apparatus. This had a 'neutral chamber' in the middle with doors on two sides, each connecting to an 'interaction chamber.' Each interaction chamber adjoined a 'stimulus cage,' which was kept separate by a wire mesh wall. They gave the test mouse time to familiarize itself with the whole apparatus before placing it back in the middle chamber and introducing a stranger - a mouse the test subject had never encountered before - into the left stimulus cage.

'The stimulus cages were just big enough for the stranger mouse to be comfy, but he couldn't approach the test mouse; only the test mouse could come toward him,' explained DeLorey. 'So the test mouse had a choice: He could be in the interaction chamber right next to the stimulus cage holding the stranger mouse, or he could be at the other end of the apparatus - as far away from that mouse as he wished.'

A normal test mouse spent about twice as much time close to the stranger mouse - sniffing, touching noses, 'trying to make friends.' Not so test mice missing the gabrb3 gene.

In the second half of the social experiments, a second stranger mouse was placed in the right stimulus cage, 10 minutes after the first stranger was introduced. Normal test mice spent more time checking out this potential new buddy, pretty much forgetting the first stranger, while knockout mice once again didn't seem to care much.

The researchers also noted that these knockout mice didn't spend much time investigating new objects placed in their testing chamber. Knockout mice also tended to be 'pretty hyper,' but while they covered a fair amount of ground with their faster movements, they also tended to run in tight circles - a classic sign of repetitive behavior.

Imaging studies have suggested that particular segments of a portion of the brain called the cerebellar vermis are smaller in people with ASD; the cerebellar vermis is also thought to be involved with attention-shifting ability. The researchers found that the relevant segments of that part of the brain were significantly smaller in the knockout mice.

DeLorey thinks it's fascinating that a mouse defective in a gene highly implicated in autism exhibits so many behavioral overlaps with human autism.

'Of course, a mouse model of a complex human disorder can't be expected to replicate a human disorder precisely,' he added. 'But it's pretty amazing that there are so many parallels observed between our mouse model and autism.'

The research was supported by the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Mental Health. Additional co-authors were Molecular Research Institute scientists Peyman Sahbaie, MD, and Ezzat Hashemi.

Alissa Poh is a science-writing intern in the School of Medicine's Office of Communication & Public Affairs.

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