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Title page for ETD etd-08012007-014955


Type of Document Dissertation
Author Zhu, Lei
Author's Email Address Lei.zhu@vanderbilt.edu
URN etd-08012007-014955
Title KCC2 and NKCC1 in the control of neuronal Cl- and brain excitability.
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Robert L. Macdonald Committee Chair
Danny G. Winder Committee Member
David M. Lovinger Committee Member
Eric Delpire Committee Member
Louis J. DeFelice Committee Member
Keywords
  • Neural transmission -- Regulation
  • GABA
  • NKCC1
  • KCC2
  • Cotransporters
  • Chlorides -- Physiological transport
  • Brain -- Growth
Date of Defense 2007-06-25
Availability unrestricted
Abstract
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.
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