The Susceptibility of Retinal Ganglion Cells to Glutamatergic Excitotoxicity Is Type-Specific

Abstract

Retinal ganglion cells (RGCs) are the only output neurons that conduct visual signals from the eyes to the brain. RGC degeneration occurs in many retinal diseases leading to blindness and increasing evidence suggests that RGCs are susceptible to various injuries in a type-specific manner. Glutamate excitotoxicity is the pathological process by which neurons are damaged and killed by excessive stimulation of glutamate receptors and it plays a central role in the death of neurons in many CNS and retinal diseases. The purpose of this study is to characterize the susceptibility of genetically identified RGC types to the excitotoxicity induced by N-methyl-D-aspartate (NMDA). We show that the susceptibility of different types of RGCs to NMDA excitotoxicity varies significantly, in which the αRGCs are the most resistant type of RGCs to NMDA excitotoxicity while the J-RGCs are the most sensitive cells to NMDA excitotoxicity. These results strongly suggest that the differences in the genetic background of RGC types might provide valuable insights for understanding the selective susceptibility of RGCs to pathological insults and the development of a strategy to protect RGCs from death in disease conditions. In addition, our results show that RGCs lose dendrites before death and the sequence of the morphological and molecular events during RGC death suggests that the initial insult of NMDA excitotoxicity might set off a cascade of events independent of the primary insults. However, the kinetics of dendritic retraction in RGCs does not directly correlate to the susceptibility of type-specific RGC death.

Deleterious Effect of NMDA Plus Kainate on the Inner Retinal Cells and Ganglion Cell Projection of the Mouse

“…Since the doses administered to induce retinal excitotoxicity injury vary according to the literature used [17,[36][37][38][39][40][41], a series of experiments were performed to determine the ideal dose of joint administration of KA and NMDA in our model. Initially, in a series of mice (n = 3-4), different individual concentrations of NMDA (10, 30 and 100 mM) and KA (5, 10 and 20 mM) were administered by intraocular injection (see above), and the density of surviving RGC was estimated.…”

“…Another factor that influences sensitivity to excitotoxic agents is the type of RGC. Thus, the Alpha RGCs are more resistant to excitotoxicity by NMDA, while other RGCs are more sensitive, which suggests the importance of cell specific neuroprotective mechanisms [17].…”

Melanopsin⁺RGCs Are Fully Resistant to NMDA-Induced Excitotoxicity

“…In adult rodents, RGCs constitute less than 1% of all retinal cells [2][3][4]. Based on their morphology (soma size and dendritic arborization), extension of their dentritic arborization into the inner synaptic layer, electrophysiological responses to light stimulus within their receptive field, target region of the brain and genetic background it has been proposed that the rodent retina may have up to 40 different types of RGCs [5][6][7][8]. In the rat it has been estimated that excluding endothelial cells, the GCL is composed of approximately 50% displaced amacrine cells (ACs), 10% glial cells, and 40% RGCs [9].…”

“…There are several markers that identify large proportions of RGCS (pan-markers) or many RGC types, including Thy-1 [12], Brn3a [13,14], RBPMS [15], class III beta-tubulin [16], Neuronal Nuclei (NeuN) [17] and Microtubule-associated protein 1A (MAP 1A) [7,18]. In addition, there are several markers that allow to identify specific types of RGCs, such as melanopsin [19] and others [7,8,20]. However, after retinal injury, many of the physiological and morphological attributes of RGCs, including their dendritic arborization may change [8,21,22], and the molecular markers may be downregulated, rendering the identification of RGCs difficult [23][24][25][26][27][28].…”

“…In addition, there are several markers that allow to identify specific types of RGCs, such as melanopsin [19] and others [7,8,20]. However, after retinal injury, many of the physiological and morphological attributes of RGCs, including their dendritic arborization may change [8,21,22], and the molecular markers may be downregulated, rendering the identification of RGCs difficult [23][24][25][26][27][28].…”