Mutation Gives Mice Autistic Symptoms

California News Correspondent

Mice with a gene mutation linked to rare human cases of autism show a hallmark symptom of the disorder: impaired social interactions. The finding, published online today in Science, adds to recent evidence that defects in the synaptic connections between neurons can contribute to autism and related conditions.

Autism is a widespread disorder characterized by social and communication difficulties and obsessive or repetitive behaviors. Scientists don't know what causes it, but genetics appears to be important. Variations in several genes have been implicated. For example, a 2003 study identified a mutation--a single-letter switch in the genetic code for a protein called neuroligin-3--in two Swedish brothers, one with autism and one with the related but milder Asperger syndrome. Neuroligin-3 resides at synapses, the communication points between neurons, but little is known about its function, let alone how it contributes to symptoms of autism.

To investigate, researchers led by Katsuhiko Tabuchi and Thomas Südhof at the University of Texas Southwestern Medical Center in Dallas created a strain of mice with the same mutation found in the Swedish brothers. The mutant mice had normal activity levels and coordination, but when the researchers put mutant mice in an enclosure with a mouse that had been restrained in a small cage, they were unusually shy, spending less time sniffing and interacting with the caged mouse than did normal mice. (The mouse had to be restrained, because otherwise it would have initiated interactions with the mutants, confounding the test.) There was no difference between mutant and normal mice when it came to investigating an empty cage, however, and the mutants even outperformed normal mice on a test of spatial learning and memory, suggesting that their deficit was specific for social behavior.

Next, Südhof's team examined slices of brain tissue from the mutant mice. A neuron typically receives a variety of synaptic inputs from its neighbors: some that excite it to send a message and others that inhibit that communication. Inhibitory signaling was abnormally strong in the mutant mice, the researchers found. Much more work is needed to figure out why the mutation alters inhibitory signaling and, in turn, how that might impair social behavior, Südhof says. Even so, he says, the findings suggest that "the synapse is where things are happening." Other recent work from Südhof and others also points in this direction (Science, 13 July).

"This is really well-done science," says Daniel Geschwind, a neurogeneticist at the University of California, Los Angeles, adding that the mice should be valuable for further autism studies. Huda Zoghbi, a geneticist at Baylor College of Medicine in Houston, Texas, agrees: "It's a great mouse to start looking at," she says. Yet Geschwind, Zoghbi, and others caution that the current findings may not apply to all cases of autism. Extremely few human cases of the disorder are caused by mutated genes for neuroligin and related proteins, notes Edwin Cook, an autism researcher at the University of Illinois Medical Center in Chicago. "We don't know how much this mechanism is going to generalize," Cook says.

Related sites

Posted in Biology, Health, Brain & Behavior