Spain, William JTao, Wucheng2015-02-242015-02-242015-02-242014Tao_washington_0250E_13883.pdfhttp://hdl.handle.net/1773/27563Thesis (Ph.D.)--University of Washington, 2014Classically, GABAB receptors regulate neurotransmission primarily through presynaptic mechanisms that inhibit neurotransmitter release, and thus inhibit GABAA receptor function. Many studies have shown that postsynaptic GABAB receptors have no direct functional effects on GABAA receptors. In this thesis, I describe novel results that indicate postsynaptic GABAB receptors activation enhances GABAA receptor function in dentate gyrus granule cells (DGGCs). During my early experiments on DGGCs, I made the surprising observation that inhibition of GABAB receptors reduced the amplitude of currents mediated by GABAA receptors. Intrigued by this exciting and unexpected result, I shifted my research to address the following three questions: 1) Do GABAB receptors regulate GABAA receptor function? 2) What are the molecular mechanisms responsible for enhancement of GABAA currents following GABAB receptor activation? and 3) What are the signaling pathways involved in this modulation? Based on these questions, I divide my thesis contents into four chapters. Chapter 1 presents an introductory review of GABAA receptors and GABAB receptors and a summary of my thesis. The main parts of this thesis with descriptions of results addressing the three questions above are presented in chapter 2 - 4: In chapter 2, I found that in dentate gyrus granule cells, postsynaptic GABAB receptor activation enhanced extrasynaptic GABAA receptor function with no effect on synaptic GABAA receptors. Specially, this modulation was cell type specific and only occurs in cell type with delta subunit-containing GABAA receptors. Also, this modulation did not occur at resting condition and required increase of ambient GABA concentration; in chapter 3, I found GABAB receptor activation increased surface expression of delta subunit-containing GABAA receptors with no change in its total protein expression or single channel conductance or channel kinetics of GABAA receptors; in chapter 4, I found that GABAB receptor modulation of GABAA receptors required two signaling pathways, one was mediated by PKA and other one was PKC; and these two signaling pathways worked in opposite directions to modulate surface expression of delta subunit-containing GABAA receptors and GABA currents. As DGGCs act as a gate for hippocampus to prevent excessive excitation inputs from entorhinal cortex, the mechanisms (enhancement of tonic inhibition by membrane trafficking of delta subunit-containing GABAA receptors) I found here maybe utilized by DGGCs to enhance their gating role.application/pdfen-USCopyright is held by the individual authors.extrasynaptic GABA-A receptor; GABA-B receptor; PKA; PKCPhysiologyphysiology and biophysicsThesis