Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer
Jingxing Ou, … , Wei Li, Paul A. Sieving
Jingxing Ou, … , Wei Li, Paul A. Sieving
Published July 1, 2015; First published June 22, 2015
Citation Information: J Clin Invest. 2015;125(7):2891-2903. https://doi.org/10.1172/JCI81380.
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Categories: Research Article Ophthalmology

Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer

Abstract

Strategies aimed at invoking synaptic plasticity have therapeutic potential for several neurological conditions. The human retinal synaptic disease X-linked retinoschisis (XLRS) is characterized by impaired visual signal transmission through the retina and progressive visual acuity loss, and mice lacking retinoschisin (RS1) recapitulate human disease. Here, we demonstrate that restoration of RS1 via retina-specific delivery of adeno-associated virus type 8-RS1 (AAV8-RS1) vector rescues molecular pathology at the photoreceptor–depolarizing bipolar cell (photoreceptor-DBC) synapse and restores function in adult Rs1-KO animals. Initial development of the photoreceptor-DBC synapse was normal in the Rs1-KO retina; however, the metabotropic glutamate receptor 6/transient receptor potential melastatin subfamily M member 1–signaling (mGluR6/TRPM1-signaling) cascade was not properly maintained. Specifically, the TRPM1 channel and G proteins Gαo, Gβ5, and RGS11 were progressively lost from postsynaptic DBC dendritic tips, whereas the mGluR6 receptor and RGS7 maintained proper synaptic position. This postsynaptic disruption differed from other murine night-blindness models with an electronegative electroretinogram response, which is also characteristic of murine and human XLRS disease. Upon AAV8-RS1 gene transfer to the retina of adult XLRS mice, TRPM1 and the signaling molecules returned to their proper dendritic tip location, and the DBC resting membrane potential was restored. These findings provide insight into the molecular plasticity of a critical synapse in the visual system and demonstrate potential therapeutic avenues for some diseases involving synaptic pathology.

Authors

Jingxing Ou, Camasamudram Vijayasarathy, Lucia Ziccardi, Shan Chen, Yong Zeng, Dario Marangoni, Jodie G. Pope, Ronald A. Bush, Zhijian Wu, Wei Li, Paul A. Sieving

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Figure 4

RS1 expression in AAV8-scRS/IRBP-hRS1–injected and uninjected Rs1-KO mice at 2 months after treatment (P92).

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RS1 expression in AAV8-scRS/IRBP-hRS1–injected and uninjected Rs1-KO mic...
Retinal sections from treated (right eye) and untreated (left eye) eyes of Rs1-KO mice 2 months after treatment, along with age-matched (P92) C57BL/6 WT mice were immunolabeled with anti-RS1 and anti-Gαo antibodies. RS1 gene transfer into Rs1-KO mice retina leads strong expression of RS1 protein (red) in inner segments (IS) of photoreceptors and OPL similar to that seen in WT mouse retina (A and C). Labeling was also prominent, but to a lesser extent, in ONL, INL, and IPL. In treated retinas, BCs staining with Gαo (green) revealed absence of schisis and much organized BC layer arrangement (F) as in WT retina (D), whereas the untreated retinas from Rs1-KO mice showed no RS1 labeling and displayed schisis cavities and BC disorganization (B and E). (G–I) Gαo-RS1 overlay. Scale bars: 30 μm. n = 3.