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Kun Do Rhee, Arlene A Hirano, Derek Teng, Christopher Luan, Xian-Jie Yang; Alleviation of Synaptic Disruption in a Mouse Model of Retinitis Pigmentosa by CNTF. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2502. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
CNTF has been shown to protect photoreceptors from degeneration in various retinal degeneration models. FDA has approved the use of CNTF-secreting encapsulated cell therapy for the treatment of retinitis pigmentosa and dry AMD. Currently, CNTF is being evaluated in clinical trials for MacTel and glaucoma. We have shown previously that in a mouse model of retinitis pigmentosa caused by rds/peripherin2 (P216L) mutation, constitutive expression of CNTF by lentivirus enhances photoreceptor viability without significant improvement of ERG. In this study, we examine whether abnormality in synaptic connection may have contributed to the lack of functional improvement by CNTF.
A lentiviral vector (LV-hCNTF) was used to express the same secreted CNTF used in clinical trials. Subretinal delivery of LV-hCNTF was performed in rds (P216L) mice at postnatal day 25 and the eyes were harvested at P31. Photoreceptor pre- and post-synaptic markers along with retinal cell type markers were used to analyze synaptic status using confocal microscopy.
In the rds (P216L) mutant, the distribution of ribbon synaptic markers Ribeye and Bassoon were significantly diminished in the rod presynaptic terminal when compared to the wild-type. LV-hCNTF infection resulted in increased density of these two synaptic markers, resembling that of the wild-type. Photoreceptor presynaptic terminal marker PSD95 and postsynaptic marker mGluR6 were also decreased in the rds (P216L) mutant. In addition, unlike the highly concentrated mGluR6 at the photoreceptor-bipolar synapses in the wild-type retina, mGluR6 was mislocalized in bipolar soma. CNTF treatment increased the levels of PSD95 and mGluR6 proteins, but did not completely alleviate mGluR6 mislocalization in bipolar neurons.
These results demonstrate that subretinal delivery of LV-hCNTF alleviates the deterioration of synaptic connections between photoreceptors and bipolar interneurons in the rds (P216L) retina. However, some persisting synaptic disruption, such as mGluR6 mislocalization, may lead to functional abnormality.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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