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

Ian Christensen,Kevin Huang,Ping Wang,Ning Yang,Ning Tian,Bo Lu

doi:10.3389/fnins.2019.00219

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.

Highlights

Morphological types of Retinal ganglion cells (RGCs) in this mouse (Xu et al, 2010). To determine whether this mouse could serve as a model to study type specific RGC death in retinal diseases, we quantified the number and dendritic structure of YFP-expressing RGCs with the approach we previously used in our study (Xu et al, 2010)
To test whether the extent of RGC dendritic retraction is correlated to the death rate of RGCs in a type-specific manner, we examined the kinetics of dendritic retraction of αRGCs, BDRGCs and JamB expressing RGCs (J-RGCs) in response to NMDA excitotoxicity using time lapse imaging on an ex vivo retinal preparation (Xu et al, 2010). αRGCs can be recognized based on their dendritic pattern in Thy1-YFP mice (Xu et al, 2010)
Our results show that the susceptibility of different types of genetically identified RGCs to NMDA excitotoxicity varies significantly

Summary

Introduction

Retinal ganglion cells (RGCs) are the only output neurons that conduct visual signals from the eyes to the brain and they are classified into at least 40 types using a combination of morphological, functional and genetic features (Badea and Nathans, 2004; Völgyi et al, 2005; Kim et al, 2008; Briggman and Euler, 2011; Briggman et al, 2011; Kay et al, 2011; Sanes and Masland, 2015; Baden et al, 2016; Rheaume et al, 2018). Increasing evidence suggests that RGCs are susceptible to various injuries in a type-specific manner. RGC Susceptibility to NMDA Toxicity of optic nerve injury, OFF RGCs were found to be more susceptible than ON RGCs, and ON sustained RGCs seem to be more susceptible than ON transient RGCs (Puyang et al, 2017). Recent studies have suggested that different types of RGCs could have unique gene expression patterns (Siegert et al, 2009; Madisen et al, 2012; Sanes and Masland, 2015) and the same genes expressed by RGCs could protect some type of RGCs but facilitate the death of other types of RGCs (Norsworthy et al, 2017). An understanding of the type-specific vulnerability of RGCs based on their gene expression may provide insights into the molecular mechanisms of neurodegeneration and suggest novel treatment strategies

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