Retinal Glutamate Neurotransmission: From Physiology to Pathophysiological Mechanisms of Retinal Ganglion Cell Degeneration

Abstract

Glutamate neurotransmission and metabolism are finely modulated by the retinal network, where the efficient processing of visual information is shaped by the differential distribution and composition of glutamate receptors and transporters. However, disturbances in glutamate homeostasis can result in glutamate excitotoxicity, a major initiating factor of common neurodegenerative diseases. Within the retina, glutamate excitotoxicity can impair visual transmission by initiating degeneration of neuronal populations, including retinal ganglion cells (RGCs). The vulnerability of RGCs is observed not just as a result of retinal diseases but has also been ascribed to other common neurodegenerative and peripheral diseases. In this review, we describe the vulnerability of RGCs to glutamate excitotoxicity and the contribution of different glutamate receptors and transporters to this. In particular, we focus on the N-methyl-d-aspartate (NMDA) receptor as the major effector of glutamate-induced mechanisms of neurodegeneration, including impairment of calcium homeostasis, changes in gene expression and signalling, and mitochondrial dysfunction, as well as the role of endoplasmic reticular stress. Due to recent developments in the search for modulators of NMDA receptor signalling, novel neuroprotective strategies may be on the horizon.

Evaluation of the neuroprotective efficacy of the gramine derivative ITH12657 against NMDA-induced excitotoxicity in the rat retina

“…This treatment protocol with ITH12657 resulted in substantial rescue of Brn3a + RGC (up to 72%) when compared to vehicle treatment (27%), and thus, such a treatment regime was implemented thereafter in the following experiments. It is well known that calcium channel blockade could influence retinal functionality and other pathways in a healthy animal ( Boccuni and Fairless, 2022 ). It is possible that our best results obtained when treatment was started 12 h prior to NMDA administration, were due to the fact that the molecule has the necessary time to reach the retina before activation of the death pathways induced by NMDA excitotoxicity, which is very fast and aggressive ( Vidal-Villegas et al, 2019 ).…”

Glutamatergic neuronal activity regulates angiogenesis and blood-retinal barrier maturation via Norrin/β-catenin signaling

“…Cholinergic waves propagated by starburst amacrine cells have also been implicated in the development of retinal deep plexus vessels and BRB maturation 14 . While glutamate is the predominant neurotransmitter in the retina during vascular development and in adulthood 70 , nothing is known about whether glutamatergic neuronal activities regulate retinal angiogenesis and BRB maturation. Our study elucidates this critical missing step that links glutamatergic neuronal activities with vascular development and maturation in the retina - a process that may also be relevant for several retinal disease.…”

Nanocarriers for the Delivery of Neuroprotective Agents in the Treatment of Ocular Neurodegenerative Diseases

“…Additionally, various studies have shown a connection between glaucoma, neuronal cell death, and the increased release of glutamate in the retina [ 68 ]. When compared to healthy people, glaucoma sufferers’ vitreous and retinal mounts showed elevated amounts of glutamate and glutamine (a metabolic precursor) and lower levels of the glutamate transporter excitatory amino acid transporter 1 [ 69 ]. This further confirms the role of neurotransmitters in the disease and needs to be studied well.…”