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NMDA receptor subunits have different roles in NMDA-induced neurotoxicity in the retina.

Bai N, Aida T, Yanagisawa M, Katou S, Sakimura K, Mishina M, Tanaka K - Mol Brain (2013)

Bottom Line: 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.However, the relative contribution of the different GluN2 subunits to RGC death by excitotoxicity remains unclear.Pharmacological inhibition of the GluN2B subunit attenuated RGC loss in glutamate aspartate transporter deficient mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. bai.ning.aud@mri.tmd.ac.jp

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

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Effects of GluN2 subunits ablation on the morphology of the retina. (A) Hematoxylin and eosin staining (H&E) of retinal sections at P35 in WT and GluN2 mutant mice. Scale bar, 50 μm. (B-C) Quantification of thickness of the inner retinal layer (B) and the cell number in the GCL (C) in WT and GluN2 mutant mice. The data are presented as mean ± S.E.M. of 5 samples for each experiment. **P <0.01. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; IRL, inner retinal layer.
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Figure 3: Effects of GluN2 subunits ablation on the morphology of the retina. (A) Hematoxylin and eosin staining (H&E) of retinal sections at P35 in WT and GluN2 mutant mice. Scale bar, 50 μm. (B-C) Quantification of thickness of the inner retinal layer (B) and the cell number in the GCL (C) in WT and GluN2 mutant mice. The data are presented as mean ± S.E.M. of 5 samples for each experiment. **P <0.01. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; IRL, inner retinal layer.

Mentions: We next investigated whether the absence of GluN2 subunits affects the anatomical organization of the retina by histological analyses. Hematoxylin and eosin staining revealed the retinae of GluN2A, GluN2Bf/f/c-kit-Cre, GluN2C, and GluN2D mutant mice to be normally organized, consisting of several different cell layers (Figure 3A). The thickness of the inner retinal layer (IRL) in all mutant strains was normal compared with wild-type (WT) mice (Figure 3B). As previous studies showed that ablation of GluN1 increased cell death in the developing somatosensory thalamus [26], we counted cell numbers in the GCL. The cell number in the GCL of GluN2Bf/f/c-kit-Cre mice was significantly lower than that of WT mice at 5 weeks, whereas cell number in the GCL of the other mutant strains was comparable to that of control mice at 5 weeks (Figure 3C). These results suggest that GluN2B subunit plays a survival role for RGCs during retinal development, but the other GluN2 subunits (GluN2A, GluN2C and GluN2D) are not involved in retinal development and survival in RGCs.


NMDA receptor subunits have different roles in NMDA-induced neurotoxicity in the retina.

Bai N, Aida T, Yanagisawa M, Katou S, Sakimura K, Mishina M, Tanaka K - Mol Brain (2013)

Effects of GluN2 subunits ablation on the morphology of the retina. (A) Hematoxylin and eosin staining (H&E) of retinal sections at P35 in WT and GluN2 mutant mice. Scale bar, 50 μm. (B-C) Quantification of thickness of the inner retinal layer (B) and the cell number in the GCL (C) in WT and GluN2 mutant mice. The data are presented as mean ± S.E.M. of 5 samples for each experiment. **P <0.01. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; IRL, inner retinal layer.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Effects of GluN2 subunits ablation on the morphology of the retina. (A) Hematoxylin and eosin staining (H&E) of retinal sections at P35 in WT and GluN2 mutant mice. Scale bar, 50 μm. (B-C) Quantification of thickness of the inner retinal layer (B) and the cell number in the GCL (C) in WT and GluN2 mutant mice. The data are presented as mean ± S.E.M. of 5 samples for each experiment. **P <0.01. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; IRL, inner retinal layer.
Mentions: We next investigated whether the absence of GluN2 subunits affects the anatomical organization of the retina by histological analyses. Hematoxylin and eosin staining revealed the retinae of GluN2A, GluN2Bf/f/c-kit-Cre, GluN2C, and GluN2D mutant mice to be normally organized, consisting of several different cell layers (Figure 3A). The thickness of the inner retinal layer (IRL) in all mutant strains was normal compared with wild-type (WT) mice (Figure 3B). As previous studies showed that ablation of GluN1 increased cell death in the developing somatosensory thalamus [26], we counted cell numbers in the GCL. The cell number in the GCL of GluN2Bf/f/c-kit-Cre mice was significantly lower than that of WT mice at 5 weeks, whereas cell number in the GCL of the other mutant strains was comparable to that of control mice at 5 weeks (Figure 3C). These results suggest that GluN2B subunit plays a survival role for RGCs during retinal development, but the other GluN2 subunits (GluN2A, GluN2C and GluN2D) are not involved in retinal development and survival in RGCs.

Bottom Line: 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.However, the relative contribution of the different GluN2 subunits to RGC death by excitotoxicity remains unclear.Pharmacological inhibition of the GluN2B subunit attenuated RGC loss in glutamate aspartate transporter deficient mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. bai.ning.aud@mri.tmd.ac.jp

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus