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Rearing light intensity affects inner retinal pathology in a mouse model of x-linked retinoschisis but does not alter gene therapy outcome

Marangoni, Dario; Yong, Zeng; Kjellström, Sten LU ; Vijayasarathy, Camasamudram; Sieving, Paul A. and Bush, Ronald A (2017) In Investigative Ophthalmology and Visual Science 58(3). p.1656-1664
Abstract

PURPOSE. To test the effects of rearing light intensity on retinal function and morphology in the retinoschisis knockout (Rs1-KO) mouse model of X-linked retinoschisis, and whether it affects functional outcome of RS1 gene replacement. METHODS. Seventy-six Rs1-KO mice were reared in either cyclic low light (LL, 20 lux) or moderate light (ML, 300 lux) and analyzed at 1 and 4 months. Retinal function was assessed by electroretinogram and cavity size by optical coherence tomography. Expression of inward-rectifier K+ channel (Kir4.1), water channel aquaporin-4 (AQP4), and glial fibrillary acidic protein (GFAP) were analyzed by Western blotting. In a separate study, Rs1-KO mice reared in LL (n = 29) or ML (n = 27) received a... (More)

PURPOSE. To test the effects of rearing light intensity on retinal function and morphology in the retinoschisis knockout (Rs1-KO) mouse model of X-linked retinoschisis, and whether it affects functional outcome of RS1 gene replacement. METHODS. Seventy-six Rs1-KO mice were reared in either cyclic low light (LL, 20 lux) or moderate light (ML, 300 lux) and analyzed at 1 and 4 months. Retinal function was assessed by electroretinogram and cavity size by optical coherence tomography. Expression of inward-rectifier K+ channel (Kir4.1), water channel aquaporin-4 (AQP4), and glial fibrillary acidic protein (GFAP) were analyzed by Western blotting. In a separate study, Rs1-KO mice reared in LL (n = 29) or ML (n = 27) received a unilateral intravitreal injection of scAAV8-hRs-IRBP at 21 days, and functional outcome was evaluated at 4 months by electroretinogram. RESULTS. At 1 month, no functional or structural differences were found between LL- or ML-reared Rs1-KO mice. At 4 months, ML-reared Rs1-KO mice showed significant reduction of b-wave amplitude and b-/a-wave ratio with no changes in a-wave, and a significant increase in cavity size, compared to LL-reared animals. Moderate light rearing increased Kir4.1 expression in Rs1-KO mice by 4 months, but not AQP4 and GFAP levels. Administration of scAAV8-hRS1-IRBP to Rs1-KO mice showed similar improvement of inner retinal ERG function independent of LL or ML rearing. CONCLUSIONS. Rearing light conditions affect the development of retinal cavities and post-photoreceptor function in Rs1-KO mice. However, the effect of rearing light intensity does not interact with the efficacy of RS1 gene replacement in Rs1-KO mice.

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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Electroretinogram, Gene therapy, OCT, Rearing light, Rs1-KO mouse
in
Investigative Ophthalmology and Visual Science
volume
58
issue
3
pages
9 pages
publisher
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
external identifiers
  • scopus:85015319990
ISSN
0146-0404
DOI
10.1167/iovs.16-21016
language
English
LU publication?
no
id
dc663ec3-4289-4d5f-842f-3e3450db668a
date added to LUP
2017-04-11 16:02:39
date last changed
2017-04-12 03:00:03
@article{dc663ec3-4289-4d5f-842f-3e3450db668a,
  abstract     = {<p>PURPOSE. To test the effects of rearing light intensity on retinal function and morphology in the retinoschisis knockout (Rs1-KO) mouse model of X-linked retinoschisis, and whether it affects functional outcome of RS1 gene replacement. METHODS. Seventy-six Rs1-KO mice were reared in either cyclic low light (LL, 20 lux) or moderate light (ML, 300 lux) and analyzed at 1 and 4 months. Retinal function was assessed by electroretinogram and cavity size by optical coherence tomography. Expression of inward-rectifier K<sup>+</sup> channel (Kir4.1), water channel aquaporin-4 (AQP4), and glial fibrillary acidic protein (GFAP) were analyzed by Western blotting. In a separate study, Rs1-KO mice reared in LL (n = 29) or ML (n = 27) received a unilateral intravitreal injection of scAAV8-hRs-IRBP at 21 days, and functional outcome was evaluated at 4 months by electroretinogram. RESULTS. At 1 month, no functional or structural differences were found between LL- or ML-reared Rs1-KO mice. At 4 months, ML-reared Rs1-KO mice showed significant reduction of b-wave amplitude and b-/a-wave ratio with no changes in a-wave, and a significant increase in cavity size, compared to LL-reared animals. Moderate light rearing increased Kir4.1 expression in Rs1-KO mice by 4 months, but not AQP4 and GFAP levels. Administration of scAAV8-hRS1-IRBP to Rs1-KO mice showed similar improvement of inner retinal ERG function independent of LL or ML rearing. CONCLUSIONS. Rearing light conditions affect the development of retinal cavities and post-photoreceptor function in Rs1-KO mice. However, the effect of rearing light intensity does not interact with the efficacy of RS1 gene replacement in Rs1-KO mice.</p>},
  author       = {Marangoni, Dario and Yong, Zeng and Kjellström, Sten and Vijayasarathy, Camasamudram and Sieving, Paul A. and Bush, Ronald A},
  issn         = {0146-0404},
  keyword      = {Electroretinogram,Gene therapy,OCT,Rearing light,Rs1-KO mouse},
  language     = {eng},
  month        = {03},
  number       = {3},
  pages        = {1656--1664},
  publisher    = {ASSOC RESEARCH VISION OPHTHALMOLOGY INC},
  series       = {Investigative Ophthalmology and Visual Science},
  title        = {Rearing light intensity affects inner retinal pathology in a mouse model of x-linked retinoschisis but does not alter gene therapy outcome},
  url          = {http://dx.doi.org/10.1167/iovs.16-21016},
  volume       = {58},
  year         = {2017},
}