In a comprehensive set of studies reported on Sunday in Nature, scientists have recreated several features of autism in a mouse by inactivating or “knocking out” the SHANK3 gene. The SHANK3 mice have obsessive behaviors and social avoidance which are two of the three features that autism spectrum disorders.
Mice tend to be curious of newcomers. However, the SHANK3 knockout mouse avoids new mice, repeatedly choosing an isolated enclosure away from the strangers. The obsessive behavior is manifest as over-grooming. A typical mouse will groom itself to clean its fur, but the SHANK3 knockout mouse continues this behavior obsessively, resulting in large furless swaths of skin on its back.
The SHANK3 gene encodes a protein that helps stabilize synapses between neurons. The authors showed that mice lacking this protein have less effective synapses in a part of their brains that is known to be involved habit formation and decision making, called the striatum. The involvement of the striatum is important because it is a hub that is very heavily connected with other parts brain through looping circuits.
The research team also found that neurons in the striatum are larger, with more branches, possibly as way of adding more synapses to compensate for the fact that individually each synapse is less effective. The team found that this region of the brain was larger in the knockout mouse, which mirrors a finding that has been reported in the autism literature in humans.
“Having an animal model that can teach us more about how a specific gene mutation is correlated with behavior is critically important to our understanding of the overall biology of autism,” said Andy Shih, vice president of scientific affairs at the nonprofit Autism Speaks. By understanding more about the Shank3 pathway, we will be able to identify new medicines that can help individuals with autism by supporting more effective synapse function.
Read more about the findings of Dr. Guoping Feng and his colleagues from MIT and Duke and follow the conversation on this topic on a recent blog from a meeting about Phelan-McDermid Syndrome, which involves mutations of SHANK3.