Loss-of-function mutation of serine racemase attenuates excitotoxicity by intravitreal injection of N-methyl-D-aspartate

Abstract

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.

Keywords: diabetic retinopathy; excitotoxicity; retinal ganglion cell; retrograde labeling.