Loss-of-function mutation of serine racemase attenuates excitotoxicity by intravitreal injection of N-methyl-D-aspartate.
Convincing data demonstrate that D-serine, a racemized product of serine racemase (SR), contributes to neurotoxicity. Furthermore, a line of evidence suggests that SR/D-serine contributes to retinal neurodegeneration in a diabetic retinopathy rat model and diabetic retinopathy patients. However, the connection between SR/D-serine and retinal neurodegeneration remains unclear. Herein, we report that intravitreal injection of N-methyl-D-aspartate (NMDA) induces excitotoxicity in rodent retina; this retinal neurodegeneration was attenuated in retina carrying a loss-of-function of mutation in Srr, the gene for SR, termed Srr(ochre269). Under the condition of NMDA injection, either posterior pole or middle - but not peripheral - retina from Srr(ochre269) mice was found to retain more retinal ganglion cells (RGC) than the counterpart from w/t (RGCs were identified with retrograde labeling). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining further demonstrated reduced RGC apoptosis from Srr(ochre269) compared to w/t mice under the condition of NMDA injection. Collectively, our studies demonstrate a pivotal role of SR/D-serine in retinal neurotoxicity. We demonstrated that loss-of-function mutation of the gene encoding serine racemase significantly attenuates excitotoxicity in retina; excitotoxicity accounts for retinal ganglion cell (RGC) demise in diabetic retinopathy (DR). We think that our findings deepen the current knowledge of the mechanisms of RGC degeneration.
School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.|State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
Haiyan
H
Jiang
School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.|State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
Xianwei
X
Wang
School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.|State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
He
H
Zhang
School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.|State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
Yuhua
Y
Chang
School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.|State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
Meiling
M
Feng
School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.|State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
Shengzhou
S
Wu
D000818:Animals; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D058449:Intravitreal Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000633:toxicity*; D019998:Racemases and Epimerases / Q000235:genetics*; D012160:Retina / Q000187:drug effects / Q000201:enzymology; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000201:enzymology*; D000099300:Serine Racemase
D018690:Excitatory Amino Acid Agonists; D016202:N-Methylaspartate; D019998:Racemases and Epimerases; D000099300:Serine Racemase
diabetic retinopathy; excitotoxicity; retinal ganglion cell; retrograde labeling