NMDA receptor subunits have different roles in NMDA-induced neurotoxicity in the retina
© Bai et al.; licensee BioMed Central Ltd. 2013
Received: 11 July 2013
Accepted: 29 July 2013
Published: 31 July 2013
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. 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.
GluN2B- 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.
Our 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.
KeywordsNMDA receptor GluN2B GluN2D Excitotoxicity Retina Glaucoma Glutamate transporter
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. However, its accumulation in extracellular spaces kills neurons through excitotoxic mechanisms via activation of glutamate receptors . Excitotoxic neuronal cell death is thought to be a final common pathway in various neurological diseases, ranging from acute ischemic stroke to chronic neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis [2–5]. Glutamate excitotoxicity has also 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 diabetic retinopathy [6–8], although some investigations have failed to confirm elevated glutamate concentration both in human patients with glaucoma  and in animal models of glaucoma [10, 11]. The toxic effects of glutamate on RGCs are predominantly mediated by the overstimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) due to their extreme permeability to calcium ions .
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+. However, the relative contribution of different GluN2 subunits to RGC death by excitotoxicity remains unclear.
We previously reported that NMDAR-mediated excitotoxicity contributed to the degeneration of RGCs in glutamate aspartate transporter (GLAST) deficient (KO) mice, the first animal model of normal tension glaucoma . Furthermore, we recently reported that GluN2D deficiency partially protected against the loss of RGCs in GLAST KO mice . These results suggest that other GluN2 subunits, in addition to GluN2D, may contribute to excitotoxic retinal cell death. To address this hypothesis, we examined the roles of the four different GluN2 subtypes in NMDA-induced retinal cell death using mice lacking specific GluN2 subunits. We also evaluated the neuroprotective effect of 7-hydroxy-6-methoxy-2-methyl-1-(2-(4-(trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (HON0001) , an specific GluN2B antagonist, on RGC degeneration due to glutamate excitotoxicity in GLAST KO mice.
In the present study, we report that GluN2B and GluN2D deficiency protect against NMDA-induced excitotoxic retinal cell death, but GluN2A and GluN2C deficiency have no protective effects. We also show that pharmacological blockade of GluN2B subunit attenuates RGC loss in GLAST KO mice.
NMDA receptor subunits present in mouse RGCs
Retinal structure in mice lacking GluN2 subunits
GluN2B and GluN2D deficiency prevents NMDA-induced-excitotoxic retinal cell death
A specific GluN2B antagonist, HON0001, prevents RGC death in GLAST-deficient mice
We previously reported that GluN2D deficiency prevented loss of RGCs in GLAST KO mice . These results suggest that both GluN2B and GluN2D subunits play a critical role in RGC degeneration by glutamate excitotoxicity. Therefore, an GluN2B-selective antagonist in combination with an GluN2D-selective antagonist represents an effective strategy for the management of glaucoma and various forms of retinopathy. We recently showed that Dock3 overexpression prevented excitotoxic RGC death by suppressing the surface expression of GluN2D and enhancing NMDA-mediated GluN2B degradation [15, 28]. Thus, the design of compounds capable of increasing the expression of Dock3 represents a novel strategy for the treatment of various forms of retinopathy. Previous studies also showed that calcium influx through NMDARs is modulated by LRP-1 [30, 31]. These findings may provide a novel therapeutic strategy for various forms of retinopathy that are mediated by E-containing lipoproteins through LRP-1.
The failure of GluN2C deficiency to protect RGCs from NMDA-induced excitotoxicity can be explained by the data showing that only a small number of RGCs expressed GluN2C . However, almost RGCs express GluN2A . The failure of GluN2A deficiency to protect RGCs from NMDA-induced excitotoxicity may be explained by the distinct functional properties conferred by GluN2 subunits on the receptors, and the different signaling pathway couplings [13, 33]. This variety is due to the large and divergent cytoplasmic C-terminal domains of GluN2 subunits . A previous report showed that C-terminal domains of GluN2B subunits were more lethal than GluN2A subunits, and different coupling to PSD-95/nNOS signaling cassette may contribute to differential susceptibility of GluN2 subunits to excitotoxic injury . Another possible explanation is that the location of NMDARs at synaptic or extrasynaptic sites determines the neuroprotective or neurotoxic effects of glutamate. A high level of synaptic NMDAR activity promotes neuronal survival, whereas extrasynaptic NMDAR activity promotes cell death . In the retina, GluN2B is enriched at the perisynaptic site, whereas synaptic NMDARs primarily contain GluN2A .
The number of cells in the GCL of GluN2Bf/f/c-kit-Cre mice was significantly decreased at 5 weeks. This finding is consistent with a previous study showing that NMDAR hypofunction increased neuronal death in the developing brain [26, 37]. GluN2B is a major GluN2 subunit in the immature retina ; therefore, ablation of GluN2B in the developing retina can cause excessive neuronal apoptosis, resulting in a reduction in the cell number in the GCL of GluN2Bf/f/c-kit-Cre mice. Thus, loss of GluN2B can increase RGC death in the immature retina, but protect RGCs from glutamate excitotoxicity in the adult.
We showed that GluN2B- and GluN2D-containing NMDARs played a critical role in NMDA-induced excitotoxic retinal cell death and RGC degeneration in GLAST KO mice. Inhibition of GluN2B and GluN2D activity is a potential therapeutic strategy for the treatment of several retinal diseases, including retinal ischemia, diabetic retinopathy, and glaucoma.
B6.Cg-TgN(Thy1-CFP)23Jrs/J transgenic mice (thy1-CFP mice) and c-kit-Cre transgenic mice have been described previously [17, 24]. c-kit-Cre transgenic mice were bred with ROSA-tdTomato mice  to examine Cre activity. c-kit-Cre mice were bred with GluN2Bflox/flox (GluN2B f/f ) mice  to generate GluN2B conditional knockout mice (GluN2B f/f /c-kit-Cre). The homozygous GluN2A KO (GluN2A −/− ) , GluN2C KO mice (GluN2C −/− )  and GluN2D KO mice (GluN2D −/− )  were obtained by crossing heterozygous GluN2A+/−, GluN2C+/− and GluN2D+/− mice, respectively. GLAST KO mice have been described previously [39, 40]. In all experiments, age matched WT and GluN2Bf/f littermate controls were used. All mice were of the C57BL/6 J genetic background, and all animal procedures were approved by the Animal Committee of Tokyo Medical and Dental University (0130166C).
Isolation of single ganglion cells from mouse retina and RT-PCR
5 week old Thy1-CFP mice were deeply anesthetized by diethyl ether and retinas were dissociated by using the Papain Dissociation System (Worthington Biochemical Corporation) at 37°C for 30 min. Single-CFP-expressing cell was aspirated by glass microcapillaries and placed into the PCR-tube containing 10 μl of resuspention buffer. Single-cell RT-PCR was performed using the SuperScript III CellsDirect cDNA Synthesis System (Invitrogen). Total RNA (5 μg) from whole retina were used to synthesize first-strand cDNA by using SuperScript III First-Strand Synthesis System (Invitrogen). The retina cDNA served as positive controls. The following primers were used for cDNA detection: GluN2A FWD: 5′ GTG TGC GAC CTC ATG TCC G 3′; REV: 5′ GCC TCT TGG TCC GTA TCA TCT C 3′; GluN2B FWD: 5′ CAG CAA AGC TCG TTC CCA AAA 3′; REV: 5′ GTC AGT CTC GTT CAT GGC TAC 3′; GluN2C FWD: ATC CCC GAC GGC TGA GA 3′; REV: 5′ TTC CTA GTC CAA GCA CAA AAC G 3′; GluN2D FWD: 5′ TGT GTG GGT GAT GAT GTT CGT 3′; REV: 5′ CCA CAG GAC TGA GGT ACT CAA AGA 3′; GluN1 FWD: 5′ GCC GAT TTA AGG TGA ACA GC 3′; REV: 5′ AAT TGT GCT TCT CCA TGT GC 3′; Brn3 FWD: 5′ GCA GTC TCC ACT TGG TGC TTA CTC 3′; REV: 5′ TTC CCC CTA CAA ACA AAC CTC C 3′; β-actin FWD: 5′ ATA TCG CTG CGC TGG TCG TC 3′; REV: 5′ TCA CTT ACC TGG TGC CTA GGG 3′. The thermal cycler conditions were 5 min at 94°C and then 40 cycles of 30 s at 94°C, 30 s at 60°C, and 30 s at 72°C, followed by 7 min at 72°C.
Western blot analysis
Retinas were quickly removed and homogenized in 100 μl of cold lysis buffer (50 mM Tris–HCl, 1% Nonidet P-40, 5 mM EDTA, 150 mM NaCl, 0.5% Na-deoxycholate, 1 mM MgCl2, 1 mM DTT, 1 mM Na3VO4, 1 mM NaF, 1 mM phenylmethylsulfonyl fluoride (PMSF), and Complete Protease Inhibitor Cocktail [Roche]). Protein concentration was determined by BCA Protein Assay kit (Sigma-Aldrich). Thirty microgram of the protein was loaded per lane. Primary antibodies used were GluN2A (1:500, Covance), GluN2B (1:500) , GluN2C (1:100, Invitrogen), GluN2D (1:500) , β-actin (1:1000, Santa Cruz). They were then incubated with anti-rabbit, guinea pig or mouse IgG-HRP-conjugated secondary antibody (1:5000, Jackson ImmunoResearch). SuperSignal West Femto Maximum Sensitivity Substrate (Thermo Scientific) was used to visualize the immunoreactive proteins.
Sections were prepared as previously described . Frozen retinal sections of 12 μm thickness were incubated using anti-Brn3 (1:50, Santa Cruz), anti-calretinin (1:500, Swant) and anti-GluN2B (1:100) antibodies. For Brn3 and calretinin detection, Cy-3-conjugated donkey anti-goat IgG (1:500, Jackson ImmunoResearch) and goat anti-rabbit IgG Alexa 488 (1:1000, Molecular Probes) were used as secondary antibodies. For GluN2B detection, peroxidase labelled polymer conjugated to goat anti-rabbit IgG (DAKO) was used as secondary antibody. Images were recorded with an LSM-510 META confocal laser microscope (Carl Zeiss).
Histology and morphometric analysis
Eyes from mice at postnatal day 35 (P35) were enucleated and fixed in Davidson’s solution fixative , then embedded in paraffin wax. In some experiments, HON0001 (10 mg/kg, a gift from T. Honda at Hoshi University)  or saline was injected orally (p.o.) into GLAST KO mice daily from P21 to P35. These mice were sacrificed on P35 and processed for RGC count. Paraffin sections (7 μm thick) were cut though the optic nerve and stained with hematoxylin and eosin (H&E). The number of neurons in the GCL was counted as previously described . The thickness of the IRL (from GCL to INL) was measured at a distance of 0.5 to 1.0 mm from optic disc.
Animal models of NMDA-induecd retinal neuronal death and morphometric analysis
Intravitreal injection of NMDA (Sigma) was conducted as previously described . Briefly, a single 2-μl injection of 20 mM NMDA in 0.1 M PBS (pH 7.4) was administered intravitreally into the right eye of each mouse, the same volume of PBS was administered to the contralateral (left) eye as control. The animals were sacrificed at 1 day or 7 days after injection, and eyes were enucleated for morphometric and TUNEL analysis. Paraffin sections (5 μm thick) were cut though the optic nerve and stained with H&E. The extent of NMDA-induced retinal cell death after 7 days was quantified by counts of neurons in the GCL and the thickness of the IRL. The changes of the number of ganglion cells and thickness of IRL after NMDA injection were expressed as percentages of the control eyes.
At 1 day after the NMDA or PBS injection, TUNEL staining was performed with paraffin sections (5 μm thick) according to the manufacturer’s instructions (Promega). Fluorescence detection was carried out using Alexa-fluor-568-conjugated streptavidin (Molecular Probes). TUNEL-positive cells in the GCL were counted and expressed as percentages of total DAPI stained cells in the GCL.
Statistical analyses were conducted using Student’s t-test for comparison between two samples, or one-way ANOVA followed by Bonferroni’s test for multiple comparisons, using the SPSS 17.0 software package. Data are expressed as mean ± S.E.M. P values < 0.05 were considered statistically significant.
Glutamate aspartate transporter
Inner nuclear layer
inner plexiform layer
Inner retina layer
lipoprotein receptor-related protein
Retinal ganglion cell
Reverse transcriptase polymerase chain reaction
We thank M. Watanabe and T. Honda for GluN2B and GluN2D antibody and for HON0001, respectively. We also thank Y. Hiraoka for technical support. This study was supported by “Understanding of molecular and environmental bases for brain health” executed under the Strategic Research Program for Brain Sciences from the Ministry of Education, Culture, Sports, Science and Technology, Japan (KT) and by the Ministry of health, Labor and Welfare of Japan (KT).
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