PMID- 34906600 OWN - NLM STAT- MEDLINE DCOM- 20220211 LR - 20230102 IS - 1096-0007 (Electronic) IS - 0014-4835 (Print) IS - 0014-4835 (Linking) VI - 214 DP - 2022 Jan TI - Effect of long-term chronic hyperhomocysteinemia on retinal structure and function in the cystathionine-beta-synthase mutant mouse. PG - 108894 LID - S0014-4835(21)00460-7 [pii] LID - 10.1016/j.exer.2021.108894 [doi] AB - Elevated levels of the excitatory amino acid homocysteine (Hcy) have been implicated in retinal diseases in humans including glaucoma and macular degeneration. It is not clear whether elevated Hcy levels are pathogenic. Models of hyperhomocysteinemia (Hhcy) have proven useful in addressing this including mice with deficiency in the enzyme cystathionine beta-synthase (CBS). Cbs(+/-) mice have a approximately two-fold increase in plasma and retinal Hcy levels. Previous studies of visual function and structure in Cbs(+/-) mice during the first 10 months of life revealed mild ganglion cell loss, but minimal electrophysiological alterations. It is not clear whether extended, chronic exposure to moderate Hhcy elevation will lead to visual function loss and retinal pathology. The present study addressed this by performing comprehensive analyses of retinal function/structure in 20 month Cbs(+/-) and Cbs(+/+) (WT) mice including IOP, SD-OCT, scotopic and photopic ERG, pattern ERG (pERG), and visual acuity. Eyes were harvested for histology and immunohistochemical analysis of Brn3a (ganglion cells), dihydroethidium (oxidative stress) and GFAP (gliosis). The analyses revealed no difference in IOP between groups for age/strain. Visual acuity measured approximately 0.36c/d for mice at 20 months in Cbs(+/-) and WT mice; contrast sensitivity did not differ between groups at either age. Similarly SD-OCT, scotopic/photopic ERG and pERG revealed no differences between 20 month Cbs(+/-) and WT mice. There was minimal disruption in retinal structure when eyes were examined histologically. Morphometric analysis revealed no significant differences in retinal layers. Immunohistochemistry revealed approximately 5 RGCs/100 mum retinal length in both Cbs(+/-) and WT mice at 20 months. While there was greater oxidative stress and gliosis in older (20 month) mice versus young (4 month) mice, there was no difference in these parameters between the 20 month Cbs(+/-) and WT mice. We conclude that chronic, moderate Hhcy (at least due to deficiency of Cbs) is not accompanied by retinal structural/functional changes that differ significantly from age-matched WT littermates. Despite considerable evidence that severe Hhcy is toxic to retina, moderate Hhcy appears tolerated by retina suggesting compensatory cellular survival mechanisms. CI - Copyright (c) 2021. Published by Elsevier Ltd. FAU - Xiao, Haiyan AU - Xiao H AD - Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, USA. FAU - Wang, Jing AU - Wang J AD - Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, USA. FAU - Barwick, Shannon R AU - Barwick SR AD - Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, USA. FAU - Yoon, Yisang AU - Yoon Y AD - James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, USA; Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, USA. FAU - Smith, Sylvia B AU - Smith SB AD - Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA, USA; Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, USA. Electronic address: sbsmith@augusta.edu. LA - eng GR - P30 EY031631/EY/NEI NIH HHS/United States GR - R01 EY012830/EY/NEI NIH HHS/United States GR - R01 EY028103/EY/NEI NIH HHS/United States GR - R21 EY031483/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20211211 PL - England TA - Exp Eye Res JT - Experimental eye research JID - 0370707 RN - 0LVT1QZ0BA (Homocysteine) RN - EC 4.2.1.22 (Cystathionine beta-Synthase) SB - IM MH - Animals MH - Chronic Disease MH - Color Vision/physiology MH - Cystathionine beta-Synthase/*genetics MH - Disease Models, Animal MH - Electroretinography MH - Female MH - Homocysteine/metabolism MH - Hyperhomocysteinemia/genetics/*physiopathology MH - Intraocular Pressure/physiology MH - Longitudinal Studies MH - Male MH - Mice MH - Mice, Inbred C57BL MH - *Mutation MH - Night Vision/physiology MH - Retina/*physiopathology MH - Tomography, Optical Coherence MH - Visual Acuity/physiology PMC - PMC9251730 MID - NIHMS1804189 OTO - NOTNLM OT - CBS mouse OT - Cystathionine beta-synthase OT - Ganglion cells OT - Homocysteine OT - Retina COIS- Declaration of competing interest None. EDAT- 2021/12/16 06:00 MHDA- 2022/02/12 06:00 PMCR- 2023/01/01 CRDT- 2021/12/15 06:00 PHST- 2021/10/08 00:00 [received] PHST- 2021/12/01 00:00 [revised] PHST- 2021/12/08 00:00 [accepted] PHST- 2021/12/16 06:00 [pubmed] PHST- 2022/02/12 06:00 [medline] PHST- 2021/12/15 06:00 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - S0014-4835(21)00460-7 [pii] AID - 10.1016/j.exer.2021.108894 [doi] PST - ppublish SO - Exp Eye Res. 2022 Jan;214:108894. doi: 10.1016/j.exer.2021.108894. Epub 2021 Dec 11.