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 June 22, 2015
Citation Information: J Clin Invest. 2015;125(7):2891-2903. https://doi.org/10.1172/JCI81380.
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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 3

Deterioration of the mGluR6-signaling machinery in adolescent Rs1-KO mice.

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Deterioration of the mGluR6-signaling machinery in adolescent Rs1-KO mic...
Gαo, Gβ5, RGS7, and RGS11 are key components of the glutamate-activated mGluR6-signaling machinery, and they appeared to be normal in expression levels and protein localization at P22 (see Figure 2, A–H, and Supplemental Figure 1). At P30, compared with WT (A and E), VGluT1 (green) proteins are no longer concentrated at the Rs1-KO photoreceptor synaptic terminals (B and F). Meanwhile, in both WT and Rs1-KO retinas, RGS7 (red) proteins are concentrated at the dendritic tips of the BCs counterstained with PKCα antibody (blue), even though the OPL and BCs have been disorganized in the mutant retinas (WT: A, I, and M; Rs1-KO: B, J, and N). Costaining of RS1 (green), RGS11 (red), and Gβ5 (blue) showed that at P30, in WT retinas (C, G, K, and O), RGS11 and Gβ5 proteins are mostly distributed to the ON-BC dendritic tips, with minor portions at the cell somas, while RS1 proteins remain at dendritic shafts. (D, H, L, and P) RS1 proteins have been absent in Rs1-KO retinas. In addition to the normal dendritic tip localization, RGS11 and Gβ5 proteins are prominently expanded toward the soma and axon of the BCs in Rs1-KO retinas (L and P). Compared with WT (Q and R), Gαo proteins in Rs1-KO retinas (S and T) also showed a prominent localization at the ON-BC somas and axons. Scale bars: 20 μm. n = 3.