Shank and zinc mediate an AMPA receptor subunit switch in developing neurons
Abstract/Contents
- Abstract
- Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders characterized by social communication deficits and restricted or repetitive behaviors. Despite the growing number of diagnosed children worldwide (from 1 in 150 in 2000 to 1 in 59 in 2014), there are no effective pharmacotherapies, underscoring the need to study the underlying biological mechanisms. Twin and family studies have emphasized the high heritability of ASDs (~ 40 %). Further genetic analyses have revealed over 100 genes linked to ASDs, many of which encode for synaptic proteins and affect the function of excitatory synapses, including members of the Shank family of postsynaptic proteins. While the genetic heritability of autism is high, environmental factors (such as prenatal zinc deficiency) might promote the development of ASDs. Intriguingly, zinc has been shown to be an important regulator of synaptic function and to bind and activate two Shank family members (Shank2 and Shank3), suggesting that zinc deficit may impair synaptic function by compromising the activation of Shank proteins by inducing conformation changes or affecting the interaction between Shanks and other synaptic molecules. At present, the means through which zinc and Shank proteins modulate synaptic function is unclear. Studies outlined in this dissertation explore whether zinc and Shanks mechanistically regulate the activity of AMPA receptors (AMPAR), a major group of glutamate receptor mediating the majority of excitatory synaptic transmission in the nervous system. My results show that the zinc-sensitive Shank proteins (Shank2 and Shank3) exhibited increased synaptic localization during early development in a similar manner to that of GluA2, suggesting both molecules might play roles in synaptic AMPAR maturation. As an initial test of this hypothesis I examined whether neural activity regulates the levels of postsynaptic zinc at glutamatergic synapses, and whether this activity is associated with the localization of Shanks and AMPAR. Using live-cell imaging, I found that K+-induced neuronal depolarization elevated postsynaptic zinc transiently and reversibly. This elevated zinc was found to enhance synaptic efficacy by recruiting GluA2 to Shank-dependent synapses. Importantly, loss of either Shank2 or Shank3 function abolished the zinc-induced enhancement of AMPAR-mediated transmission, suggesting that Shanks are critical mediators of a zinc-AMPAR signaling. Together, these data provide a mechanistic link between genetic mutations in Shanks and prenatal zinc deficiency in the etiology of ASD.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Ha, Huong Thi Thanh |
|---|---|
| Degree supervisor | Huguenard, John |
| Thesis advisor | Huguenard, John |
| Thesis advisor | Ding, Jun (Jun B.) |
| Thesis advisor | Garner, Craig |
| Thesis advisor | Madison, Daniel V, 1956- |
| Degree committee member | Ding, Jun (Jun B.) |
| Degree committee member | Garner, Craig |
| Degree committee member | Madison, Daniel V, 1956- |
| Associated with | Stanford University, Neurosciences Program. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Huong Thi Thanh Ha. |
|---|---|
| Note | Submitted to the Neurosciences Program. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Huong Thi Thanh Ha
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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