Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, February 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 134-157). / Autism and autism spectrum disorders (ASDs) are clinically defined by the symptoms of social impairment and repetitive behavior, affecting 1 in 68 children in the United States. Because patients with ASDs typically display symptoms before the age of three, the ASDs are classically categorized as developmental disorders. One of the key questions in autism research is whether the pathology is reversible in adults. Many studies of simple sensory systems have reported that there is a distinct critical period for synaptic plasticity. This is most famously supported by the monocular deprivation studies in young kittens, which resulted in irreversible visual impairment in adulthood (Hubel and Wiesel, 1970). However, it is not clear whether this principle extends to more complicated multi-modal behavioral systems. Here we demonstrate that adult rescue can lead to improvements in selective phenotypes of ASD by generating and using a novel Shank3 conditional knock-in mouse model. Estimated to contribute to about 1% of all ASD cases, Shank3 is one of the most prominent genes associated with autism. It is a master postsynaptic scaffolding protein that mediates synaptic plasticity and remodeling by regulating many neurotransmitter receptors including NMDAR, AMPAR, and numerous actin-binding regulators. Disruptions of Shank3 in mouse models have robustly recapitulated the cardinal phenotypes of autism including anxiety, social interaction deficits, and compulsive/stereotyped behavior. By specifically expressing Shank3 in adult mice that were initially born as Shank3 knockouts, we show that deficits in the synaptic protein composition and striatal neurotransmission can be fully recovered. We developed a novel neuronal tracing technique to study the dendritic spine density, and found that the dendritic spine number is also significantly increased in the rescue condition after development. In addition, we show that while anxiety and motor coordination are not improved, social interaction and repetitive behavior can be significantly rescued. This suggests that plasticity for certain neural circuits persist into adulthood in the diseased brain, and that the underlying mechanisms for different autistic-like phenotypes have distinct properties. / by Yuan (Karen) Mei. / Ph. D.
| Identifer | oai:union.ndltd.org:MIT/oai:dspace.mit.edu:1721.1/106438 |
| Date | January 2016 |
| Creators | Mei, Yuan (Yuan Karen) |
| Contributors | Guoping Feng., Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences., Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences. |
| Publisher | Massachusetts Institute of Technology |
| Source Sets | M.I.T. Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 157 pages, application/pdf |
| Rights | M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission., http://dspace.mit.edu/handle/1721.1/7582 |
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