Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Ophthalmology Article has an altmetric score of 14

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

  • Text
  • PDF
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

×

Figure 5

RS1 gene transfer restores photoreceptor calcium homeostasis and TRPM1 functionality in Rs1-KO retinas.

Options: View larger image (or click on image) Download as PowerPoint

RS1 gene transfer restores photoreceptor calcium homeostasis and TRPM1 ...
Rs1-KO retinas were injected with AAV8-scRS/IRBP-hRS1 viruses at P30 and examined at P92. At P92, compared with WT retinas, the untreated Rs1-KO retinas had a disrupted OPL with scattered signals of RIBEYE (purple, B and C) and low abundance of the TRPM1 channel (green, E and F) at the OPL, while treated Rs1-KO retinas revealed improved lamination of the OPL and the close proximity of the presynaptic ribbon to the TRPM1 channels at the ON-BC dendritic tips (D and G). (A) Functional rescue by RS1 gene transfer. Increases in rod photoreceptor synaptic free calcium concentration (untreated: 35% of that in WT; treated: 69% of that in WT [n = 4; *P < 0.05, Student’s t test]); TRPM1 intensity at ON-BC dendritic tips (percentage of whole-cell TRPM1 signal intensity; untreated: 37%; treated: 45% [n = 4; ***P < 0.001, Student’s t test]); and light-adapted RBC MP: untreated retina –37 ± 1.4 mV vs. treated retina –29.2 ± 1.2 mV (n = 4; ***P < 0.001, Student’s t test); WT retina –28.3 ± 1.4 mV. All Rs1-KO values were normalized to that of P30 WT. At P92, while VGluT1 (green) was localized at the OPL in WT retinas (H), it was scattered and less abundant at the disrupted OPL in untreated control retinas (I). Treatment led to a nearly normal appearance of VGluT1 immunoreactivity concentrated along the restored OPL of Rs1-KO retinas (J). Notably, the mGluR6 receptor (green) and RGS7 (purple) retained their normal localization at the ON-BC dendritic tips in Rs1-KO retinas regardless of the viral treatment (K and N: WT; L and O: untreated; M and P: AAV8-RS1 treated). Scale bars: 15 μm (B–G); 20 μm (H–P). n = 3.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 1 news outlets
Posted by 3 X users
Referenced in 2 patents
On 1 Facebook pages
71 readers on Mendeley
See more details