During postnatal development of the central nervous system, the response of GABAA receptor to its agonist undergoes a switch from excitatory to inhibitory, due to a developmental decrease in the intracellular Cl- concentration. In this thesis, I show that the cation chloride cotransporters KCC2 and NKCC1 regulate intracellular chloride and brain excitability. First, I provide evidence that KCC2 is responsible for the developmental decrease of intracellular [Cl-]. Second, I demonstrate that in the young adult, KCC2 is responsible for the rapid removal of chloride that is accumulated in the cell either by prolonged GABAA activation, prolonged membrane depolarization, or co-activation of GABA and glutamate receptors. Third, I show that excitability and seizure susceptibility are both increased in KCC2+/- brain slices. Finally, I demonstrate that NKCC1 decreases neuronal excitability and prevents 4-aminopyridine-induced epileptic seizure in young mice. During the course of this research, I also developed a new method to measure the membrane potential of neurons in brain slices.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08012007-014955 |
| Date | 01 August 2007 |
| Creators | Zhu, Lei |
| Contributors | Robert L. Macdonald, Louis J. DeFelice, Danny G. Winder, David M. Lovinger, Eric Delpire |
| 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-08012007-014955/ |
| 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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