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.
| Duvoisin, Robert M; Haley, Tammie L; Ren, Gaoying et al. (2017) Autoantibodies in Melanoma-Associated Retinopathy Recognize an Epitope Conserved Between TRPM1 and TRPM3. Invest Ophthalmol Vis Sci 58:2732-2738 |
| Guimarães-Souza, E M; Perche, O; Morgans, C W et al. (2016) Fragile X Mental Retardation Protein expression in the retina is regulated by light. Exp Eye Res 146:72-82 |
| Brown, R Lane; Xiong, Wei-Hong; Peters, James H et al. (2015) TRPM3 expression in mouse retina. PLoS One 10:e0117615 |
| Neuillé, Marion; Morgans, Catherine W; Cao, Yan et al. (2015) LRIT3 is essential to localize TRPM1 to the dendritic tips of depolarizing bipolar cells and may play a role in cone synapse formation. Eur J Neurosci 42:1966-75 |
| Reed, Brian T; Morgans, Catherine W; Duvoisin, Robert M (2013) Differential modulation of retinal ganglion cell light responses by orthosteric and allosteric metabotropic glutamate receptor 8 compounds. Neuropharmacology 67:88-94 |
| Fendt, M; Bürki, H; Imobersteg, S et al. (2010) The effect of mGlu8 deficiency in animal models of psychiatric diseases. Genes Brain Behav 9:33-44 |
| Jeffrey, Brett G; Morgans, Catherine W; Puthussery, Theresa et al. (2010) R9AP stabilizes RGS11-G beta5 and accelerates the early light response of ON-bipolar cells. Vis Neurosci 27:9-17 |
| Zhang, Jianmei; Jeffrey, Brett G; Morgans, Catherine W et al. (2010) RGS7 and -11 complexes accelerate the ON-bipolar cell light response. Invest Ophthalmol Vis Sci 51:1121-9 |
| Quraishi, S; Reed, B T; Duvoisin, R M et al. (2010) Selective activation of mGluR8 receptors modulates retinal ganglion cell light responses. Neuroscience 166:935-41 |
| Morgans, Catherine W; Zhang, Jianmei; Jeffrey, Brett G et al. (2009) TRPM1 is required for the depolarizing light response in retinal ON-bipolar cells. Proc Natl Acad Sci U S A 106:19174-8 |
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