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Shank synaptic genes in autism: Human genetics to mouse models and therapeutics

May 24, 2011 10 comments

This is a guest post by by Mehreen Kouser, a Dennis Weatherstone Fellow, and Ph.D. Candidate working with Dr. Craig Powell at the UT Southwestern.

This year IMFAR hosted a Scientific Panel titled “Shank synaptic genes in autism: Human genetics to mouse models and therapeutics” organized and chaired by Dr. Craig Powell. This panel consisted of four presentations starting with the unequivocal role of Shank3 in autism and ending with potential treatment strategies in genetically mutated mouse models of Shank3.

Over the past few years , Shank3 has emerged as the new “it” gene for autism. Current estimates suggest that Shank3 errors account for 0.5-2 % of autism diagnoses making it a major genetic cause of  autism. Several recent human studies have implicated mutations/deletions/duplications in the Shank family of proteins, especially Shank3, to be involved in ASD and 22q13 Deletion Syndrome.  Shank3 is a scaffolding protein that is involved in synapse architecture. Mutations in Shank3 are known to affect synaptic connections between neurons in similar ways to other autism-relevant genes such as neuroligin and neurexin. Thus understanding the role of Shank3 in autism is critical.

The first presenter at this panel was Dr. Catalina Betancur from INSERM in France. Dr. Betancur was a major player in the discovery of Shank3’s relevance to autism.  She carefully detailed all known human mutations, deletions, and duplications published since the first paper on Shank3 mutations in idiopathic autism was published in 2007.She also outlined the case for Shank3 as a major causative gene in the symptoms of the 22q13 chromosomal deletion syndrome known as Phelan-McDermid Syndrome.   In addition, Dr. Betancur detailed the work of her laboratory and others implicating Shank2, another member of the Shank gene family, in autism.

Dr. Joseph Buxbaum from Mount Sinai School of Medicine in New York was the next presenter. His laboratory was the first to publish a genetic mouse model of Shank3 successfully Shank3.  Their Shank3 mutant mouse closely mimics autism-associated mutations in this area of the Shank3 gene.  His work focused on the heterozygous mutation of Shank3 gene as this is the state of autism patients with Shank3 mutations. Characterization of this mouse model, clearly suggests that Shank3 plays an important role in synapse architecture, function, and plasticity. Among the most intriguing findings in his presentation was his ability to reverse the manifestations of Shank3 mutation in brain slices treated with Insulin-like Growth Factor-1 (IGF-1). This gives us the much needed hope that Shank3 mutation models of autism will lead to identification of novel therapeutic targets that can be validated in these models.

Next, Dr. Yong-hui Jiang from Duke University in North Carolina presented his work on a genetic mouse model very similar to that of Dr. Buxbaum’s group, but his focus was the homozygous mutation of Shank3 mutating both copies of the gene. He noted that the Shank3 gene is more complex than originally thought, with potentially having as many as six variants or isoforms. His careful analysis of this mutant model clarified that only a portion of Shank3 isoforms are affected by this genetic strategy.  He identified abnormalities in synaptic connection  morphology in his model.  Moreover, his lab characterized this mouse model extensively on autism related behaviors and found them to be impaired in the social behaviors, repetitive behaviors, communication, motor coordination and learning and memory. These results demonstrate that human diseases can be successfully modeled in mice. The hope is that if we can reverse them in mice, treatments for humans are not far away.

Dr. Joao Peca from Guoping Feng’s lab at MIT in Massachusetts concluded the session by presenting a completely different Shank3 mutation in mice.  He began his presentation by telling us about another synaptic gene called SAPAP3 and showing us its involvement in a repetitive grooming behavior in mice. He showed that SAPAP3 knockout mice continuously groom themselves and that this behavior can be reversed by putting this gene back into the striatum of mice later in life. He also showed that Shank3 is a strong binding partner of SAPAP3 and their Shank3 mutant mice have the same increase in repetitive grooming behaviors.   Like the other Shank3 mutations, this mutant does not affect all forms of Shank3, but may mimic a different human mutation.

This panel set the stage for future advances in the area of Shank3 and autism.  Only 4 years after the initial study implicating Shank3 in autism, we now have at least 3 different animal models and 4 publications on these models.  Although, we may face grave challenges in sorting through the heterogeneity of mutations, deletions, and duplications and their different consequences, these presenters clearly demonstrate that this strategy will lead to identification of potential therapeutic targets that can be readily tested in animal models.

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.

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