Autism mutations in ProSAP2/Shank3 disrupt zinc-dependent dynamics and transsynaptic signaling
Abstract/Contents
- Abstract
- Autism spectrum disorders (ASDs) are a pervasive set of neurodevelopmental disorders that are characterized by deficits in social interaction and communication. ASDs are diagnosed in 1 out of 88 children and are more common in males. ASDs are thought to be highly heritable and a wide variety of genetic mutations have been identified, including mutations in several synaptic proteins. This dissertation research explores convergent synaptic mechanisms underlying ASDs, specifically exploring several aspects of synaptic biology that are disrupted by autism-associated mutations in the ProSAP/Shank family of postsynaptic scaffolding proteins, focusing primarily on one family member, ProSAP2/Shank3, for which the genetic data is strongest. Data collected for this thesis demonstrate that ProSAP/Shank proteins act within dendritic spines to coordinate pre- and postsynaptic changes in synaptic function by regulating the activation of Neurexin-Neuroligin signaling complexes. Intriguingly, autism mutations in ProSAP2/Shank3 were found to disrupt this transsynaptic signaling, thereby functionally linking several synaptic proteins implicated in ASDs. Mechanistic experiments revealed that ProSAP2/Shank3 activation and scaffold stability within postsynaptic densities (PSDs) are zinc-sensitive and that zinc supplementation can reactivate ProSAP2/Shank3 carrying an ASD mutations, partially or fully rescuing transsynaptic signaling. Importantly, zinc deficiencies are linked to mental retardation and thus may be a risk factor for autism by contributing to synaptic dysfunction within neuronal networks.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2012 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Arons, Magali Holt |
|---|---|
| Associated with | Stanford University, Department of Neurosciences. |
| Primary advisor | Garner, Craig |
| Thesis advisor | Garner, Craig |
| Thesis advisor | Clandinin, Thomas R. (Thomas Robert), 1970- |
| Thesis advisor | Hallmayer, Joachim |
| Thesis advisor | Reimer, Richard J |
| Thesis advisor | Shatz, Carla J |
| Advisor | Clandinin, Thomas R. (Thomas Robert), 1970- |
| Advisor | Hallmayer, Joachim |
| Advisor | Reimer, Richard J |
| Advisor | Shatz, Carla J |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Magali Holt Arons. |
|---|---|
| Note | Submitted to the Department of Neurosciences. |
| Thesis | Ph.D. Stanford University 2012 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2012 by Magali Holt Arons
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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