New research by a scientist in the University of Oregon’s Institute of Neuroscience illustrates how a gene critical to autism can be manipulated to produce behaviors of the disorder.
The findings, published in the May 29 issue of the Journal of Neuroscience, have implications for potential gene therapies and also suggest there may be narrow windows of opportunity to be effective, said principal investigator Philip Washbourne, a biology professor whose lab focuses on synapses and what goes wrong in autism.
Washbourne’s team manipulated a gene linked to autism spectrum disorders in transgenic mice, producing mature adults with irreversible deficits affecting either learning or social interaction.
Scientists were able to produce two different ends of the autism spectrum by working with the same gene, either overexpressing its normal form or a mutated version.
The research, reported by an 11-member team from three universities, targeted the impacts of alterations in the gene neuroligin 1 -- one of many genes implicated in human autism spectrum disorders. One group over-expressed the normal gene, the other a mutated version.
Mice with higher-than-normal levels of the normal gene after a month had skewed synapses at maturity. In these mice, there were clear cognitive problems.
"Behavior was just not normal,” Washbourne said. “They didn't learn very well, and they were slower to learn, but their social behavior was not impacted."
Mice over-producing a mutated version of the gene reached adulthood with structurally immature synapses.
"They were held back in development and behavior -- the way they behave in terms of learning and memory, in terms of social interaction," Washbourne said. "We saw arrested development. Learning is a little bit better, they are more flexible just like young mice, they learn faster, but their social interaction is off. To us, this looked more like Asperger's syndrome.”
Effects seen in the social behavior of mice with the mutated gene, he said, were not unlike observations reported by parents of many autistic children. While normal mice prefer to engage with new mice entering their world rather than familiar others, or even a new inanimate object, these mice split their time equally.
"It's not a deficit in memory regarding which mouse is which, it's more a weighting of their interaction,” Washbourne said. “If you talk to parents of autistic children, one of the frustrating things they report is that their children treat complete strangers in exactly the same way that they treat them."
The team also found that adjustments to improve deficits in the mice, once fully mature, were ineffective. This suggests that gene therapy may have to be applied to individuals with autism early on, Washbourne said.
Washbourne’s co-authors included seven UO colleagues: doctoral students Jennifer Hoy, Michael Kyweriga and Lawrence Davis; postdoctoral researcher John Constable; undergraduate students Renee Arias and Raluca McCallum; and Michael Wehr, professor of psychology.
While the findings provide new insights, any translation into treatment could be decades away.
"A problem with autism is there are many different genes potentially involved,” Washbourne said. “It could be that some day, if you are diagnosed with autism, a mouth swab might allow for the identification of the exact gene that is mutated and allow for targeted therapy. Autism might be like cancer, with hundreds of potential combinations of faulty genes."
- by UO Office of Strategic Communications