Tonic GABAA receptors in hippocampal pyramidal neurons and their sensitivity to general anesthetics.
Published: 2004
Language: eng
Number of pages: 245
Description: gamma-Aminobutyric acid (GABA) plays a key role in mediating inhibitory neurotransmission in the central nervous system (CNS). Several studies have shown that GABA mediates two distinct forms of inhibition: transient inhibitory postsynaptic currents (IPSCs) and tonic inhibition that is thought to be generated by extrasynaptic GABA type A (GABAA) receptors. Here, we demonstrate that the tonic form of inhibition in hippocampal pyramidal neurons is generated by a distinct subpopulation of GABAA receptors, specifically, alpha5 subunit-containing GABAA (alpha5GABAA) receptors that have different pharmacological and kinetic properties compared to postsynaptic receptors. Tonic GABAA receptors have alpha5beta2/3gamma2 pharmacological characteristics. alpha5GABAA receptors are well-suited to detect low, persistent, ambient concentrations of GABA in the extracellular space as they are highly sensitive to GABA and desensitize slowly. Several studies have shown that alpha5GABAA receptors are important in memory processes, as reduced expression or pharmacological inhibition is associated with improved memory performance. We examine the effects of low concentrations of the volatile anesthetic, isoflurane (ISO), on the tonic current and show that the alpha5 subunit is necessary for enhancement of the tonic conductance by low concentrations of ISO in hippocampal pyramidal neurons. Studies of human recombinant GABAA receptors show that low concentrations of ISO potentiate GABA-evoked current mediated by alpha5beta3gamma2L but not alpha1beta3gamma2L receptors and that ISO is more efficacious at alpha5GABAA receptors. These studies provide the foundation for investigating an association between increased tonic GABAergic inhibition in the hippocampus and the effects of anesthetics on memory.
Notes: Adviser:  Beverley A. Orser.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5008.