Title page for ETD etd-01092004-162154

Type of Document Dissertation
Author Hoffpauir, Brian Kevin
Author's Email Address bhoffpa@lsu.edu
URN etd-01092004-162154
Title Modulation of GABAergic Signaling in Retinal Amacrine Cells
Degree Doctor of Philosophy (Ph.D.)
Department Zoology (Biological Sciences)
Advisory Committee
Advisor Name Title
Evanna L. Gleason Committee Chair
Jim H. Belanger Committee Member
John T. Caprio Committee Member
Richard C. Bruch Committee Member
Robert M. Strongin Dean's Representative
  • nitric oxide
  • metabotropic glutamate receptor
  • modulation
  • gaba
  • amacrine cells
  • retina
  • electrophysiology
Date of Defense 2003-12-18
Availability unrestricted
The intricate circuitry formed by amacrine cells in the inner plexiform layer (IPL) of the retina suggests that these interneurons play a major role in shaping the visual message. The majority of amacrine cells in the vertebrate retina are GABAergic. Thus, elucidating how GABAergic signaling is modulated in the IPL is critical in order to understand how the visual message is processed in the retina. The results presented here suggest that GABAergic signaling between amacrine cells can be modulated by the activation of metabotropic glutamate receptor 5 (mGluR5) or by the production of the second messenger, nitric oxide (NO). A novel mGluR5 splice variant was isolated from the chicken retina with a truncated carboxy-terminal tail. Whole cell electrophysiological experiments indicated that activation of mGluR5 enhances GABA-gated currents recorded from cultured chick amacrine cells. This mGluR5-dependent enhancement occurred through the inositol 1,4,5-trisphosphate pathway and was dependent upon the release of Ca2+ from internal stores. The Ca2+-dependent protein kinase (PKC) was also required for the mGluR5-dependent enhancement as indicated by 1) enhancement of GABA-gated currents by PKC activators, 2) occlusion of the mGluR5-dependent enhancement by these activators, and 3) reduction of the mGluR5-dependent enhancement by a PKC inhibitor. The mGluR5-dependent enhancement of synaptic currents was nearly twice that observed for whole cell GABA-gated currents, suggesting that the receptors and signaling molecules are targeted to GABAergic synapses. NO also modulated GABAergic transmission between amacrine cells, but through two different pathways. Lower concentrations of NO released from NO donors enhanced GABA-gated currents by affecting the function of the GABAA receptors through a soluble guanylate cyclase-independent pathway. Higher concentrations of NO (NO-bubbled solutions) increased the intracellular Cl- concentration through an uncharacterized and potentially novel mechanism that possibly involves Cl- cotransporters. The NO-induced influx of Cl- shifts the Cl- equilibrium potential (ECl-) to more positive values. Furthermore, the NO-induced shift in ECl- allows GABA to depolarize the membrane potential, indicating that NO can convert an inhibitory GABAergic synapse to an excitatory synapse.
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