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MECHANISMS UNDERLYING BDNF STIMULATION OF MTOR-DEPENDENT
PROTEIN SYNTHESIS
by
Yu-Tien Hsu
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(NEUROSCIENCE)
August 2011
Copyright 2011 Yu-Tien Hsu
Object Description
| Title | Mechanisms underlying BDNF stimulation of MTOR-dependent protein synthesis |
| Author | Hsu, Yu-Tien |
| Author email | yutienh@usc.edu;yutienhsu@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts And Sciences |
| Date defended/completed | 2011-03-10 |
| Date submitted | 2011-07-14 |
| Date approved | 2011-07-15 |
| Restricted until | 2011-07-15 |
| Date published | 2011-07-15 |
| Advisor (committee chair) | Baudry, Michel |
| Advisor (committee member) |
Ko, Chien-Ping Madigan, Stephen |
| Abstract | Scientists have long been searching for ways to enhance learning and memory and to repair brain injury. Dendritic protein synthesis is now recognized as being an event essential for the formation of new synapses and the establishment of neural circuits in brain. For instance, dendritic translation of the mRNA for activity-regulated cytoskeleton-associated protein (Arc) is important for both LTP consolidation and memory formation. Importantly, memory stabilization/consolidation is protein synthesisdependent, as inhibition of mRNA translation prevents long-term storage and consolidation of newly learned tasks and events. ❧ Long-term potentiation (LTP) is a long-lasting increase in synaptic strength and is important for memory formation and stabilization in mammalian brain. Several events occur during LTP induction and consolidation, including dendritic protein synthesis and calpain activation. The calcium-dependent proteases, calpains, participate in many different signaling pathways, including apoptosis and synaptic plasticity. While it is tempting to assume that protein synthesis as well as proteolytic events would be involved in synaptic plasticity and learning and memory, the relationships and cross-regulation between these 2 processes are currently unknown. ❧ Many studies have shown that the neurotrophic factor, brain-derived nerve growth factor (BDNF) regulates neural activity, enhances synaptic activity, and activates dendritic protein synthesis. Dendritic protein synthesis is triggered by the activation of the mammalian target of rapamycin (mTOR) pathway, and requires the phosphorylation of several translation factors and protein kinases, such as the initiation factor 4E binding protein 1 (4EBP1) and p70S6 kinase (p70S6K). Recently, we demonstrated that CX614, one of the most studied positive AMPA receptor modulators (PARMs), acutely triggers BDNF release and stimulates the dendritic translation machinery by activating mTOR and the eukaryotic initiation factor 4E (eIF4E). Moreover, CX614 increases BDNF mRNA and protein levels and facilitates LTP induction. Because of its dual effect on BDNF and LTP, CX614 and other types of ampakines have been proposed to represent potential therapeutic candidates for the treatment of diseases associated with cognitive impairment. ❧ Several events occur during LTP induction and consolidation, including dendritic protein synthesis and calpain activation. Inhibition of mRNA translation prevents LTP formation and long-term storage and consolidation of newly learned tasks and events. Calpain is another crucial factor that has been shown to be involved in LTP induction. Calpain inhibitors block LTP induction in vitro in hippocampal slices and in vivo in adult rat. However, the detailed molecular mechanisms linking calpain activation to mTORdependent translation machinery remain unknown. In this dissertation, we studied the relationship between BDNF-induced calpain activation and mTOR signaling. BDNF has been shown to stimulate calpain activity and mTOR signaling in cultured neurons and acute hippocampal slices. Pre-incubation with calpain inhibitor Ш blocked BDNF induced mTOR phosphorylation/activation and increase in Arc levels, suggesting that calpain activation precedes mTOR-mediated protein synthesis. Furthermore, we found that a negative regulator of protein synthesis, the tumor suppressor PTEN, is a substrate of calpain. Following BDNF treatment of acute hippocampal slices decreased PTEN was correlated with increased mTOR phosphorylation and Arc expression. These results suggest that calpain regulates mTOR-mediated protein synthesis through PTEN degradation. We also observed a similar pattern following kainic acid-induced seizure activity, as calpain activation resulted in decreased PTEN and increased Arc levels in hippocampal CA1, CA3 and DG regions. ❧ This main goal of this dissertation was to provide a better understanding of the relationships between various BDNF-induced signaling pathways, thereby providing fundamental information regarding the molecular events involved in memory formation. A second goal of this work was to identify potential new targets for designing better treatments of mental disorders. |
| Keyword | BDNF; mTOR; calpain; protein synthesis |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Hsu, Yu-Tien |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume71/etd-HsuYuTien-90.pdf |
Description
| Title | Page 1 |
| Full text | MECHANISMS UNDERLYING BDNF STIMULATION OF MTOR-DEPENDENT PROTEIN SYNTHESIS by Yu-Tien Hsu A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (NEUROSCIENCE) August 2011 Copyright 2011 Yu-Tien Hsu |
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