June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Rod Photoreceptor-specific REV-ERBα Deletion Accelerates Age-related Synaptic Remodeling in the Mouse Retina
Author Affiliations & Notes
  • Meenakshi Maurya
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Chi-Hsiu Liu
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Kiran Bora
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Neetu Kushwah
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Madeline C Pavlovich
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Zhongjie Fu
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • James D Akula
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Jing Chen
    Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Meenakshi Maurya None; Chi-Hsiu Liu None; Kiran Bora None; Neetu Kushwah None; Madeline Pavlovich None; Zhongjie Fu None; James Akula None; Jing Chen None
  • Footnotes
    Support  This work was supported by NIH/NEI R01s (EY031765, EY024963, and EY028100) (to JC).
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4875. doi:
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    • Get Citation

      Meenakshi Maurya, Chi-Hsiu Liu, Kiran Bora, Neetu Kushwah, Madeline C Pavlovich, Zhongjie Fu, James D Akula, Jing Chen; Rod Photoreceptor-specific REV-ERBα Deletion Accelerates Age-related Synaptic Remodeling in the Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4875.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Age-related retinal synaptic remodeling comprises neuronal function, as reported both in humans and mice. Alterations in outer retinal synapses were studied as a model to explore synaptic modifications in aging. REV-ERBα (a nuclear receptor and transcription factor) regulates circadian rhythm and metabolism and is associated with synaptic strengthening in Alzheimer’s disease models. The present study explored the role of REV-ERBα in the maintenance of age-related synaptic integrity between rods and rod-bipolar cells using rod-specific REV-ERBα deficient mice.

Methods : Rod-specific conditional knockout (Rho-icre: Rev-erbαfl/fl) mice with age-matched flox controls were generated. Genetic deletion of Rev-erbα was confirmed using RT-qPCR, Western blotting, and immunohistochemistry (IHC). Synapses were visualized in 12 months-old (12 MO) Rho-icre: Rev-erbαfl/fl and flox controls by IHC with antibodies against synaptic ribbon protein Ribeye and rod bipolar cell marker PKC-α. The number and length of retracted photoreceptor synapses and outgrowth of bipolar dendrites were quantified (n=3 mice/group). LKB1, a downstream target of REV-ERBα, was quantified using immunoblotting (n=3 mice/group). The retinal visual function was assessed using scotopic ERG (12 MO, both male and female) and data were quantified (Mann-Whitney test, n=6 mice/group).

Results : REV-ERBα was localized in both rods and rod bipolar cells with IHC. In 12 MO Rho-icre: Rev-erbαfl/fl retinas, the number, and length of rod synapse retraction were significantly increased compared with flox controls, accompanied by ectopic rod bipolar cell dendrite sprouts extending into the photoreceptor layer, similar to our previous observation in 11 MO systemic Rev-erbα-/- mice. Western blot analysis revealed a significant reduction in LKB-1 level in Rho-icre: Rev-erbαfl/fl mice retina. Scotopic ERG analysis showed a significant reduction in the amplitude of rod-specific a- and b- waves, and in the sensitivity of rod b-wave only in 12 MO Rho-icre: Rev-erbαfl/fl, compared to flox controls.

Conclusions : Our findings suggest that rod-specific knockout of Rev-erbα accelerates age-related outer retina synaptic remodeling and visual function decline, potentially through regulation of photoreceptor energy and metabolism via LKB1. These data suggest a rod-intrinsic role of REV-ERBα in maintaining photoreceptor synaptic integrity during aging.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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