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 6

ERG in Rs1-KO mice showing that AAV8scRS/IRBP-hRS1 gene transfer improves synaptic function.

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ERG in Rs1-KO mice showing that AAV8scRS/IRBP-hRS1 gene transfer improve...
(A) Representative ERG waveforms (n = 3) from the treated and untreated eyes of an Rs1-KO mouse that received a unilateral injection of AAV8-scRS/IRBP-hRS1 (2.5 × 109 vg/eye) at P30 compared with responses from a WT mouse. The dark-adapted ERG b-wave amplitude recorded from the untreated eye at P90 is decreased relative to the a-wave amplitude when compared with WT, indicating a reduced postsynaptic BC response to photoreceptor signaling. The AAV8scRS/IRBP-hRS1–treated eye, however, shows a selective improvement in b-wave amplitude, resulting in a waveform more similar to that of the WT. This indicates a restoration of postsynaptic responses. The a-wave amplitude is measured from baseline (0 ms) to the negative trough; b-wave amplitude is measured from the a-wave trough to the positive peak. Stimulus flash occurs at 0 ms. Arrows indicate the a-wave implicit time (time from stimulus flash to peak amplitude) for the treated and untreated eyes. (B) The a-wave implicit time for mice injected in 1 eye with 1 μl of AAV8-RS1 at various doses or with 1 μl of vehicle. Values represent the average difference between the untreated and treated eyes (untreated – treated) at each dose. The a-wave implicit time is significantly shorter in treated eyes at doses of 1.0 × 108 vg/eye and higher. Asterisks indicate significance compared with zero, the value expected if there is no effect of treatment (*P < 0.05; ****P < 0.0001, 1-sample t test). n = 4.