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Many of the mutations that are known to be associated with autism disable protein complexes that support the outgrowth of neurons as they reach out to signal to other neurons. Morgan Sheng and his colleagues at the Massachusetts Institute of Technology aim to examine the role of these protein complexes to learn how their loss leads to the social and cognitive disabilities in autism.
Two neurons talk to each other at specialized regions of the cells called synapses. To make a synapse, neurons first generate cytoplasmic extensions known as dendritic spines. Scaffolding proteins, such as members of the Shank family, bring together the cytoskeleton and intracellular signaling factors within the dendritic spine, coordinating these pathways? activities. Once the synapse is constructed, the scaffolding proteins have other responsibilities: the Shank proteins are also important for interpreting signals at the receiving side of the synapse, specifically those signals that excite, rather than inhibit, the target cell?s activity.
Mutations in one Shank protein, Shank 3, have been found in familial cases of autism. Sheng and colleagues previously found that without another family member, Shank 1, neurons produce smaller dendritic spines and have fewer functional synapses in the developing mouse brain. In behavioral tests, mice that lack Shank 1 have mixed cognitive abilities reminiscent of autism: high sensitivity to spatial information, but low memory formation in fear conditioning.
Sheng and colleagues now plan to study mice that lack Shank 1 or Shank 3 to better understand the role of this protein family in neurological function. The researchers will examine whether the loss of Shank 1 or Shank 3 disturbs dendritic spine and synapse formation in adult mice, which would indicate a life-long role for the proteins in learning and memory. Because of the Shank proteins? role in interpreting excitatory signals, the researchers also plan to investigate the balance of inhibitory and excitatory signals in Shank 1- and Shank 3-deficient brains. This balance is precisely tuned to transmit information between different regions of the brain; disruptions in the balance could account for the abnormal processing of information seen in people with autism. Sheng and colleagues plan to look for accompanying changes in the social interactions of the Shank 1- and Shank 3- deficient mice, which might indicate an autism-like impairment in their behavior.
Ultimately, Sheng and colleagues hope that these studies also demonstrate whether the removal of these proteins creates a representative animal model of autism for future studies of mechanism and therapy.
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