Inhibition Of Non-NMDA Ionotropic Glutamate Receptors Delays Retinal Degeneration In Rd10 Mice

Purpose: Retinitis pigmentosa is a progressive neurodegenerative disease that cause deterioration of rod and cone photoreceptors and is the leading cause of blindness in the world.The aim of this study is to understand the progress of the disease focusing in the glutamate pathway,and to seek effective way to protect the function of retinal neurons,hoping to provide a new strategy to treat retinitis pigmentosa in the clinic.Methods: In our study,we used rd10 mice,a well-established animal model of retinitis pigmentosa,to detect the changes of glutamate receptors expression during photoreceptor degeneration and the impact on the function of retinal ganglion cells.We firstly checked the changes of ON signal cascade proteins(metabotropic glutamate receptor 6,m Glu R6 and TRPM1 protein)and OFF signal cascade related ionotropic glutamate receptors(i Glu Rs)by immunostaining.Then we used multi-electrode-array(MEA)system to record the light response of ganglion cells and the effects of perfusing low dose of CNQX(non-NMDA i Glu Rs antagonist)on the functions of retinal ganglion cells.Lastly,we i.p.injected rd10 mice with CNQX for 2 weeks,and examined the changes of light response of ganglion cells and the morphology of retinal neurons,as well as the animal behavior.Results: m Glu R6 and TRPM1 were down-regulated in the outer plexiform layer during photoreceptors degeneration.In contrast,i Glu Rs were up-regulated in the inner plexiform layer,and AMPA receptors formed abnormal clusters in the outer plexiform layer.During photoreceptors degeneration,the light response of ganglion cells in rd10 retina decreased while the spontaneous spiking increased abnormally.Both in vitro and in vivo application of low-dose CNQX inhibited the abnormal spontaneous spiking and increased the light evoked response of ganglion cells.Furthermore,in vivo application of CNQX increased the survival of photoreceptors,improved the morphology of bipolar cells as well as the behavioral performance.Conclusion: Our data indicate that blocking the ionotropic glutamate signal pathway by CNQX delays the functional decay of ganglion cells during photoreceptors degeneration,thus it might be an effective strategy to prolong the time window for the treatment of retinitis pigmentosa.