Regulation of axonal transport mediates in vivo en passant pre-synapse formation
Abstract/Contents
- Abstract
- In order for the brain to function, neural circuits must be wired to form appropriate connections, called synapses, during development. In order to assemble the synapse at a given location, all the materials which comprise the pre-synaptic neurotransmitter release apparatus and post-synaptic receptors must be assembled in opposition to each other. Since neurons are specialized types of cells, understanding these processes requires us to understand how materials are synthesized by the cell, travel from their sites of synthesis to the axons/dendrites, where the majority of synapses are located, and then come together to form a synapse. This thesis will focus on these key cell-biological questions as they pertain to the assembly of the pre-synaptic neurotransmitter release apparatus. More specifically, in my thesis I ask how do two key components of synapses, Synaptic Vesicles (SVs) and Active Zone proteins (AZs) travel to the synapse from their sites of synthesis? What motors are responsible? How are cargoes dropped off at synapses, both during development and during later stages of maintenance and plasticity when synaptic materials must be re-supplied? In Chapter 1 of my thesis, I introduce more detailed conceptual and molecular background to frame these questions, including what is currently understood about the axon cytoskeleton and axon transport of pre-synaptic materials. The second part of chapter 1 consists of a review I wrote on what is currently known about AZ protein axonal transport. In Chapter 2 of my thesis, I describe work I did to contribute to a project that investigated this process of SVP cargo drop-off. Specifically, we find that auto-inhibition of the Kinesin-3 motor by an intra-molecular binding interaction between the motor head and motor tail domain is essential to get SVs that are properly distributed among many en passant synapses. Chapter 3 of my thesis is a study that I initiated with Kang to understand how pre-synaptic terminals first form behind an extending growth cone during development, and how SVs and AZ proteins are transported from the cell body to these nascent synaptic sites. In this study, I investigate the development of pre-synaptic terminals in PDE dopaminergic neurons in C. Elegans. First, I show that PDE dopamine neurons contain bona fide active zones, characterized by the presence of canonical AZ proteins. Then, focusing on the development of these synapses, I find that PDE pre-synapses, characterized by SVs clustered at active zones, form rapidly behind the extending growth cone, in many cases, appearing in as little as a few minutes. SVs are clearly dependent upon Kinesin-3 for transport down the axon and to synapses, and pausing of the Kinesin motor by auto-inhibition is crucial to deposition of these SVs at en passant synapses, even during the earliest stage of development. In contrast, different AZs exhibit differential dependence on Kinesin-3 for transport, with most AZ proteins being Kinesin-3 independent.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2017 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Lipton, David Matthew |
|---|---|
| Associated with | Stanford University, Neurosciences Program. |
| Primary advisor | Shen, Kang, 1972- |
| Thesis advisor | Shen, Kang, 1972- |
| Thesis advisor | Clandinin, Thomas R. (Thomas Robert), 1970- |
| Thesis advisor | Luo, Liqun, 1966- |
| Thesis advisor | McConnell, Susan |
| Advisor | Clandinin, Thomas R. (Thomas Robert), 1970- |
| Advisor | Luo, Liqun, 1966- |
| Advisor | McConnell, Susan |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | David Matthew Lipton. |
|---|---|
| Note | Submitted to the Program in Neurosciences. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2017. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2017 by David Matthew Lipton
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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