Abstract
BackgroundLoss of retinal ganglion cells (RGCs) is a hallmark of various retinal diseases including glaucoma, retinal ischemia, and diabetic retinopathy. N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR)-mediated excitotoxicity is thought to be an important contributor to RGC death in these diseases. Native NMDARs are heterotetramers that consist of GluN1 and GluN2 subunits, and GluN2 subunits (GluN2A–D) are major determinants of the pharmacological and biophysical properties of NMDARs. All NMDAR subunits are expressed in RGCs in the retina. However, the relative contribution of the different GluN2 subunits to RGC death by excitotoxicity remains unclear.ResultsGluN2B- and GluN2D-deficiency protected RGCs from NMDA-induced excitotoxic retinal cell death. Pharmacological inhibition of the GluN2B subunit attenuated RGC loss in glutamate aspartate transporter deficient mice.ConclusionsOur data suggest that GluN2B- and GluN2D-containing NMDARs play a critical role in NMDA-induced excitotoxic retinal cell death and RGC degeneration in glutamate aspartate transporter deficient mice. Inhibition of GluN2B and GluN2D activity is a potential therapeutic strategy for the treatment of several retinal diseases.
Highlights
Loss of retinal ganglion cells (RGCs) is a hallmark of various retinal diseases including glaucoma, retinal ischemia, and diabetic retinopathy
NMDA receptor subunits present in mouse RGCs To investigate the expression of N-methyl-D-aspartate receptor (NMDAR) subunits in RGCs, we used a single-cell reverse transcriptase polymerase chain reaction (RT-PCR) method
GluN2B and GluN2D deficiency prevents NMDA-inducedexcitotoxic retinal cell death To determine which GluN2 subtypes are involved in NMDA-induced RGC death in the retina, we examined the effect of intraocular injection of NMDA on retinal cell death in GluN2 KO and WT mice
Summary
Loss of retinal ganglion cells (RGCs) is a hallmark of various retinal diseases including glaucoma, retinal ischemia, and diabetic retinopathy. N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR)-mediated excitotoxicity is thought to be an important contributor to RGC death in these diseases. Glutamate excitotoxicity has been proposed to be an important contributor to the death of retinal ganglion cells (RGCs) in glaucoma and ischemia-related conditions such as vessel occlusion and NMDARs are composed of various combinations of GluN1 and GluN2 (GluN2A–GluN2D) subunits and, in some cases, GluN3 (GluN3A and GluN3B) subunits. GluN2 subunits are major determinants of the functional properties of NMDARs, including characteristics such as agonist affinity, deactivation kinetics, single-channel conductance, Ca2+ permeability, and sensitivity to Mg2+ [13]. The relative contribution of different GluN2 subunits to RGC death by excitotoxicity remains unclear
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