Molecular mechanisms of signal transduction in retina

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DESCRIPTION (provided by applicant): Glutamate is the major excitatory neurotransmitter in the vertebrate CNS. In the retina it is the neurotransmitter used along the feed-forward pathway from photoreceptors, to bipolar cells, to ganglion cells. Glutamatergic transmission is mediated by glutamate receptors, of which there are two broad classes: lonotropic glutamate receptors are ligand-gated ion channels. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors and their function is mediated by second messenger pathways. The objective of this project is to determine the distribution and function of group-Ill mGluRs in the inner plexiform layer of the retina. Group-Ill mGluRs are selectively activated by L-2-amino-4-phosphonobutyric acid (APB, also abbreviated L-AP4) and consist of mGluR4, -R6, -R7, and -R8. mGluR6 is present in ON bipolar cell dendrites and mediates the depolarizing response of these cells to light, generating the ON visual pathway. While the other group-Ill mGluRs are known to be widely expressed in the brain, indicating that they may be involved in a number of pathologies, their precise distribution and function in the retina is poorly characterized. Group-Ill mGluRs are currently tested as targets for therapeutic drugs, and it is important to know what effects on vision these drugs may have. Moreover, because the expression of group-Ill mGluRs is not restricted to the retina, a better understanding of their function in the retina will have broader significance for our understanding of normal and pathological brain function. In the retina, we hypothesize that group-Ill mGluRs are present in bipolar cell terminals and in amacrine cells where they regulate neurotransmitter release. The specific aims of this project are 1) to localize immunohistochemically group-Ill mGluRs in the rabbit retina; 2) to determine the effects of mGluR4, -R7 and -R8 stimulation on the light responses of starburst amacrine and ganglion cells; and 3) to determine the role of group-Ill mGluRs in the generation of photopic ERG oscillatory potentials.