MOLECULAR MECHANISMS OF SIGNAL TRANSDUCTION IN RETINA

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DESCRIPTION (Adapted from applicant's abstract): In the retina, specialized synapses transmit the graded hyperpolarization induced by light stimuli in photoreceptors to the second order neurons, i.e., and bipolar and horizontal cells. At these ribbon synapses, the neurotransmitter glutamate is continuously released in the dark and stimulates glutamate receptors on postsynaptic cells (AMPA/kainate-type receptors on horizontal and OFF-bipolar cells; mGluR6 on ON bipolar cells). The metabotropic glutamate receptor mGluR8, which we recently cloned, is present in the photoreceptor terminal. We hypothesize that there, as in the hippocampus and olfactory system, it may be providing a negative-feedback regulation of glutamate release. We recently generated transgenic mice in which mGluR8 has been inactivated by homologous recombination. We will use these animals, as well as cell lines that express mGluR8 or mutant mGluR8 to address the following specific aims: (1) whether photoreceptor synapses and retinal development are altered by the absence of mGluR8 in transgenic animals lacking this receptor; (2) what the signal transduction pathway is linking mGluR8 activation to a modulation of intracellular calcium level and, presumably, glutamate release; (3) what controls the localization of mG1uR8 to axon terminals; and (4) how this proposed negative-feedback regulation of mGluR8 on photoreceptor glutamate release shapes the light responses of bipolar cells. This aim will be done in collaboration with Rowland Taylor (John Curtin School of Medical Research) who is currently uniquely able to perform such experiments. The proposed regulation of synaptic transmission by mGluR8 at the photoreceptor ribbon synapse is likely to be important for vision since at this synapse, the membrane potential changes produced by phototransduction are converted into a modulation of neurotransmitter release.