Abstract
The chick is rapidly becoming a standardized preclinical model in vision research to study mechanisms of ocular disease. We seek to comprehensively evaluate the N-methyl-D-aspartate (NMDA) model of excitotoxic retinal damage using multimodal imaging, functional, and histologic approaches in NMDA-damaged, vehicle-treated, and undamaged chicks. Chicks were either left undamaged in both eyes or were injected with NMDA in the left eye and saline (vehicle) in the right eye. TUNEL assay was performed on chicks to assess levels of retinal cell death one day post-injection of NMDA or saline and on age-matched untreated chicks. Spectral domain optical coherence tomography (SD-OCT) was performed weekly on chicks and age-matched controls day 1 (D1) up to D28 post-injection. Light adapted electroretinograms (ERG) were performed alongside SD-OCT measurements on post-injection chicks along with age-matched untreated controls. Untreated and vehicle-treated eyes had no TUNEL positive cells while NMDA-treated eyes accumulated large numbers of TUNEL positive cells in the Inner Nuclear Layer (INL), but not other layers, at D1 post injection. Significant inner retina swelling or edema was found on SD-OCT imaging at D1 post-injection which resolved at subsequent timepoints. Both the INL and the inner plexiform layer significantly thinned by one-week post-injection and did not recover for the duration of the measurements. On ERG, NMDA-treated eyes had significantly reduced amplitudes of all parameters at D1 with all metrics improving over time. The b-wave, oscillatory potentials, and ON/OFF bipolar responses were the most affected with at least 70% reduction immediately after damage compared to the fellow eye control. This study establishes a normative baseline on the retinal health and gross functional ability as well as intraocular pressures of undamaged, vehicle-treated, and NMDA-damaged chicks to provide a standard for comparing therapeutic treatment studies in this important animal model.
Highlights
Animal models are critical to understand the mechanisms of retinal disease and potential treatments
Significant inner retina swelling or edema was found on Spectral domain optical coherence tomography (SD-OCT) imaging at day 1 (D1) post-injection which resolved at subsequent timepoints
Both the Inner Nuclear Layer (INL) and the inner plexiform layer significantly thinned by one-week post-injection and did not recover for the duration of the measurements
Summary
Animal models are critical to understand the mechanisms of retinal disease and potential treatments. Glutamate excitotoxicity occurs when a surplus of glutamate, a neurotransmitter, forms in the retina due to either excessive release or inadequate clearance by glutamine synthetase [4,5,6] This excess glutamate activates NMDA receptors on inner retinal neurons which function as Ca2+ pumps into the cells. The resulting increase in intracellular Ca2+ acts as a second messenger and triggers a cascade that leads to eventual cell death [7,8,9,10,11,12] This cell death can occur through both apoptotic and necrotic pathways depending on the glutamate or NMDA concentration [7]. The NMDA retinal damage model simulates glutamate excitotoxicity by injecting NMDA into the vitreous cavity, which will activate the NMDA receptor, and cause Ca2+ induced cell death [14]
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