Exogenous Zinc Ions Interrupt Signal Transmission From Photoreceptors To Bipolar Cells And Reduce Retinal TRPM1Expression In Mouse

Purpose: Transient receptor potential cation channel subfamily Mmember1(TRPM1) on the retinal ON-bipolar cells plays a crucial role invisual transmission. Previous studies indicated zinc ions were inhibitors ofTRPM1in vertebrate in vitro. We determined whether zinc ions affectretinal signal transmission and TRPM1in mammals.Methods: C57BL/6J mice were randomly divided into control andexperimental group. The experimental mice received unilateral intravitrealinjections of0.4μl0.01M zinc sulfate solution and the control micereceived injections of same volume of phosphate buffer solution (PBS).Dark-and light-adapted electroretinogram (ERG) was recorded at1hour,1day,1week,4weeks and8weeks after injection. Western blotting wasemployed to assay TRPM1protein expressions in the retina. PKCα andCtBP2immunofluorescence (IF) was performed to detect the morphologicchanges of rod bipolar cells and photoreceptor synaptic structures. Inaddition,50μl of0.05M zinc sulfate solution was injected intravitreally ina rhesus monkey. ERG ON-OFF responses were recorded at2hours after injection.Results: From1hour to8weeks after zinc injections, the mouseERGs exhibited similar changes and a negative ERG waveform wasevident: the amplitudes of dark-and light-adapted ERG b-waves weredramatically decreased while the a-waves appeared normal. Similar ERGswere also observed in the zinc-injected monkey eye. Furthermore, theON-OFF ERG responses of the monkey showed a prominently attenuationof the b-wave but an unaffected a-wave. Western blotting indicatedTRPM1protein expression was decreased in the zinc-treated mouse retina.Morphology showed retinal structures were unchanged at day1after zincinjection. However, at8weeks after injection, the inner retina particularlythe inner nuclear layer (INL) became thinner, the number of rod ONbipolar cell decreased. Meanwhile, aberrant dendritic processes of rodbipolar cells projected into the outer nuclear layer (ONL). The number ofthe photoreceptor synaptic ribbon decreased and ectopic ribbons were seenin the ONL of zinc-treated retina.Conclusion: Exogenous zinc ions interrupted retinal signaltransmission from photoreceptors to ON bipolar cells but barely affectedphotoreceptor functions. Zinc downregulated TRPM1expression implyingmGluR6-Gα0-TRPM1may be a potential target of zinc mediatedinterruption instantly after injection. Abnormalities of inner retina structuremay contribute to the long term defects of ON pathway dysfunction.