GABA functions as the primary inhibitory neurotransmitter in the mammalian brain. In hippocampus, GABA serves multiple roles during development and throughout adulthood, which include: 1) orchestrate synapse maturation and synaptogenesis, 2)
maintain inhibitory synaptic transmission, and 3) regulate the excitability and synchronize the neuronal output of principal neurons. Because normal brain function requires intact inhibitory synaptic transmission, interneurons must possess mechanisms to adapt synaptic GABA during a wide range of activity states. I hypothesized that one effective mechanism may involve regulating GABA synthesis and vesicular GABA content through modulating the supply of glutamine, an indirect GABAergic metabolic precursor, by System A glutamine transporters. In addition, because GABA serves critical roles during early hippocampal development we hypothesized that the role of
System A transporters at inhibitory synapses also may be developmentlally regulated. Therefore, this dissertation explored if modulation of System A surface activity dynamically regulated GABA synthesis and inhibitory synaptic transmission in response to changing developmental and neuronal activity states. Using electrophysiology in hippocampal slices in conjunction with protein expression studies and uptake assays in synaptosomes, I demonstrate that System A transporters serve both a constitutive and activity-dependent role in modulating vesicular GABA content and inhibitory synaptic strength. Synaptic depolarization up-regulates the surface activity of System A transporters and thus induces an increase in vesicular GABA content in both immature and mature hippocampus. However, because System As basal uptake activity and therefore its constitutive contribution to vesicular GABA content diminishes over the first two postnatal weeks, its role in mature hippocampus is only manifest in an activity-dependent manner. Furthermore, my results support that these constitutive and activitydependent roles are likely mediated by the SNAT1 subtype of System A transporters. Therefore, my findings strongly support the hypothesis that the surface activity of SNAT1, regulated both by depolarization and by developmental cues, is the key component in a novel mechanism to dynamically link metabolic demand for GABA with vesicular GABA content and inhibitory synaptic strength.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03292010-151906 |
| Date | 10 April 2010 |
| Creators | Brown, Molly Nicole |
| Contributors | Gregory C. Mathews, Randy Blakely, Michael Aschner, Danny Winder, Gregg Stanwood |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03292010-151906/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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