Developing Stage-dependent Retinal Toxicity Induced by l-glutamate in Neonatal Rats

Abstract

The neurotransmitter glutamate causes excitotoxicity in the human retina. In neonatal rats, the degree of glutamate-induced retinal damage depends on age at administration. To elucidate the sensitivity to glutamate on various developing stage of retina, we investigated glutamate-induced retinal damage and glutamate target cells on each postnatal day (PND). Newborn rats received a single subcutaneous administration of l-glutamate on PNDs 1 to 14. Retinal cell apoptosis characterized as pyknotic and terminal deoxynucleotidyl transferase–mediated dUTP digoxigenin nick end labeling–positive nuclei was analyzed at 6 hr after treatment, and sequential morphological features of retina were evaluated on PND 21. The inner retina on PND 21 exhibited thinning in rats treated after PND 2. The thinning was most severe in rats treated on PND 8 and the number of apoptotic cells also peaked. No thinning was observed in rats treated on PND 14. In the inner nuclear layer, glutamate target cells were mainly amacrine cells; additionally, bipolar cells and horizontal cells were damaged on PND 8. These retinal changes were more severe in central retina than those in peripheral retina on PND 8. Our findings indicate the morphological consequences of glutamate-induced retinal excitotoxicity and glutamate target cells on each PND and reveal that glutamate-induced retinal damage depends on developing stage.