Posts Tagged ‘mouse’

New SHANK3 model animal

March 23, 2011 13 comments

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.

5|25: Celebrating Five Years of Autism Science Day 8: Creation of Neuroligin-3 Mutant Mouse

February 8, 2010 Leave a comment

In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our eighth item, Creation of Neuroligin-3 Mutant Mouse, is from Autism Speaks’ Top 10 Autism Research Events of 2007.

Animal models have long been employed to replicate some of the behavioral and biochemical characteristics of autism. The models are chosen for study either because they have behaviors reminiscent of autism, or because they have received genetic or environmental manipulations believed to be linked, directly or indirectly, to autism.

Yet, only with the recent progress of detailed genetic studies in developmental disorders have these models been based on the actual genetic differences found in humans with autism. Some of these newer models for autism include mouse models of medical genetic syndromes that show overlap with autism, e.g., Fragile X syndrome, Rett syndrome and Tuberous Sclerosis. However, no model existed that contained the precise genetic defect found in anyone whose autism is not caused by one of these other genetic syndromes. This changed in October 2007, when researchers in Texas reported they had succeeded in replacing the mouse neuroligin-3 gene with a human version containing the exact mutation discovered in 2004 to be the cause of autism in a Swedish family with two affected brothers. Excitingly, the initial exploratory studies have found the “humanized neuroligin-3″ mouse has several unusual behaviors, including deficits in some social behaviors and an increased ability for spatial learning in a swimming test.

This mouse provided the research community with a strong new tool to directly assess the neurobiology, behavioral deficits and, conceivably soon enough, treatment approaches for autism. Such models are a vital part of the drug discovery process because measurement of changes in their behaviors can be used as surrogate markers for preclinical evaluation of new therapeutics.

Since this story was first run: Genetic studies continue to provide new opportunities for the generation of animal models of autism, including many related to the function of the neuroligins. In 2009 the same group of researchers carried out a behavioral characterization of mice lacking the neurexin-1alpha gene, which creates proteins that serve as binding partners for the neuroligins. Published in the Proceedings of the National Academies of Science, the scientists have now discovered that the neurexin-1alpha mice have abnormal brain physiology and increased repetitive behaviors.


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