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Age and Visual Experience-dependent Expression of NMDAR1 Splice Variants in Rat Retina

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Abstract

The N-methyl-D-aspartate receptor (NMDAR) is a key molecule mediating brain plasticity related processes. Knowing that alternative splicing of the NMDAR1 (NR1) subunit offers molecular diversity to NMDAR, controls the forward trafficking of the NR1 protein and is important for placing NMDA receptors at synapses, we investigated herein the postnatal developmental expression and the influence of visual deprivation on NR1 subunit splice variants in rat retina. Real-time PCR was performed using oligonucleotide primers specific for N- terminal (NR1a, NR1b) and C-terminal splice variants (NR1-1, NR1-2, NR1-3, NR1-4). The developmental profiles of mRNA expression levels of all NR1 isoforms peaked at the end of the third week. Dark rearing led to reductions in both N- and C-terminal NR1 variants in several developmental ages and a significant interaction between age and visual experience was observed for NR1a, NR1-2 and NR1-4 expression. Our results have demonstrated a developmental and visual experience-dependent regulation of NR1 splicing in rat retina.

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References

  1. Hollmann M, Heinemann S (1994) Cloned glutamate receptors. Ann Rev Neurosci 17:31–108

    Article  PubMed  CAS  Google Scholar 

  2. Bear MF, Kleinschmidt A, Gu QA et al (1990) Disruption of experience-dependent synaptic modifications in striate cortex by infusion of an NMDA receptor antagonist. J Neurosci 10:909–925

    PubMed  CAS  Google Scholar 

  3. Roberts EB, Meredith MA, Ramoa AS (1998) Suppression of NMDA receptor function using antisense DNA block ocular dominance plasticity while preserving visual responses. J Neurophysiol 80:1021–1032

    PubMed  CAS  Google Scholar 

  4. Monyer H, Sprengel R, Schoepfer R et al (1992) Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256:1217–1221

    Article  PubMed  CAS  Google Scholar 

  5. Nakanishi N, Axel R, Shneider NA (1992) Alternative splicing generates functionally distinct N-methyl-D-aspartate receptors. Proc Nat Acad Sci 89:8552–8556

    Article  PubMed  CAS  Google Scholar 

  6. Sugihara H, Moriyoshi K, Ishii T et al (1992) Structures and properties of seven isoforms of the NMDA receptor generated by alternative splicing. Biochem Biophys Res Commun 185:826–832

    Article  PubMed  CAS  Google Scholar 

  7. Durand GM, Gregor P, Zheng X et al (1992) Cloning of an apparent splice variant of the rat N-Methyl–d-aspartate receptor NMDAR1 with altered sensitivity to polyamines and activators of protein kinase C. Proc Nat Acad Sci 89:9359–9363

    Article  PubMed  CAS  Google Scholar 

  8. Tingley WG, Roche KW, Thompson AK (1993) Regulation of NMDA receptor phosphorylation by alternative splicing of the C-terminal domain. Nature 364:70–73

    Article  PubMed  CAS  Google Scholar 

  9. Ehlers MD, Tingley WG, Huganir RL (1995) Regulated subcellular distribution of the NR1 subunit of the NMDA receptor. Science 269:1734–1737

    Article  PubMed  CAS  Google Scholar 

  10. Tingley WG, Ehlers MD, Kameyama K et al (1997) Characterization of protein kinase A and protein kinase C phosphorylation of the N-Methyl–D-aspartate receptor NR1 subunit using phosphorylation site-specific antibodies. J Biol Chem 272:5157–5166

    Article  PubMed  CAS  Google Scholar 

  11. Okabe S, Miwa A, Okado H (1999) Alternative splicing of the C-terminal domain regulates cell surface expression of the NMDA receptor NR1 subunit. J Neurosci 19:7781–7792

    PubMed  CAS  Google Scholar 

  12. Standley S, Roche KW, McCallum J et al (2000) PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants. Neuron 28:887–898

    Article  PubMed  CAS  Google Scholar 

  13. Perez-Otano I, Ehlers MD (2005) Homeostatic plasticity and NMDA receptor trafficking. Trends Neurosci 28:229–238

    Article  PubMed  CAS  Google Scholar 

  14. Lau CG, Zukin RS (2007) NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 8:413–426

    Article  PubMed  CAS  Google Scholar 

  15. Hollmann M, Boulter J, Maron C et al (1993) Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor. Neuron 10:943–945

    Article  PubMed  CAS  Google Scholar 

  16. Traynelis SF, Hartley M, Heinemann SF (1995) Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines. Science 268:873–876

    Article  PubMed  CAS  Google Scholar 

  17. Koltchine VV, Anantharam V, Bayley H et al (1996) Treistman SN. Alternative splicing of the NMDAR1 subunit affects modulation by calcium. Mol Brain Res 39:99–108

    Article  PubMed  CAS  Google Scholar 

  18. Thoreson WB, Witkovsky P (1999) Glutamate receptors and circuits in the vertebrate retina. Prog Retin Eye Res 18:765–810

    Article  PubMed  CAS  Google Scholar 

  19. Brandstätter JH, Hartveit E, Sassoè-Pognetto M et al (1994) Expression of NMDA and high-affinity kainate receptor subunit mRNAs in the adult rat retina. Eur J Neurosci 6:1100–1112

    Article  PubMed  Google Scholar 

  20. Watanabe M, Mishina M, Inoue Y (1994) Differential distributions of the NMDA receptor channel subunit mRNAs in the mouse retina. Brain Res 634:328–332

    Article  PubMed  CAS  Google Scholar 

  21. Kreutz MR, Böckers TM, Bockmann J et al (1998) Axonal injury alters alternative splicing of the retinal NR1 receptor: the preferential expression of the NR1b isoform is crucial for retinal ganglion cell survival. J Neurosci 18:8278–8291

    PubMed  CAS  Google Scholar 

  22. Hatrtveit E, Brandstätter JH, Sassoè-Pognetto M et al (1994) Localization and developmental expression of the NMDA receptor subunit NR2A in the mammalian retina. J Comp Neurol 348:570–582

    Article  Google Scholar 

  23. Fletcher E, Hack I, Brandstätter JH et al (2000) Synaptic localization of NMDA receptor subunits in the rat retina. J Comp Neurol 420:98–112

    Article  PubMed  CAS  Google Scholar 

  24. Gründer T, Kohler K, Kaletta A et al (2000) The distribution and developmental regulation of NMDA receptor subunit proteins in the outer and inner retina of the rat. J Neurobiol 44:333–342

    Article  PubMed  Google Scholar 

  25. Pourcho RG, Quin P, Goebel DJ (2001) Cellular and subcellular distribution of NMDA receptor subunit NR2B in the retina. J Comp Neurol 433:75–85

    Article  PubMed  CAS  Google Scholar 

  26. Kalloniatis M, Sun D, Foster L et al (2004) Localization of NMDA receptor subunits and mapping NMDA drive within the mammalian retina. Vis Neurosci 21:587–597

    Article  PubMed  Google Scholar 

  27. Chang YC, Chen CY, Chiao CC (2010) Visual experience-independent functional expression of NMDA receptors in the developing rabbit retina. Invest Ophthalmol Vis Sci 51:2744–2754

    Article  PubMed  Google Scholar 

  28. Xue J, Li G, Bharucha E et al (2002) Developmentally regulated expression of CaMKII and iGluRs in the rat retina. Brain Res Dev Brain Res 138:61–70

    Article  PubMed  CAS  Google Scholar 

  29. Laurie DJ, Seeburg PH (1994) Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA. J Neurosci 14:3180–3194

    PubMed  CAS  Google Scholar 

  30. Paupard MC, Friedman LK, Zukin RS (1997) Developmental regulation and cell-specific expression of N-methyl-D-aspartate receptor splice variants in rat hippocampus. Neuroscience 79:399–409

    Article  PubMed  CAS  Google Scholar 

  31. Lee-Rivera I, Zarain-Herzberg A, López-Colomé AM (2003) Developmental expression of N-Methyl-D-aspartate glutamate receptor 1 splice variants in the chick retina. J Neurosci Res 73:369–383

    Article  PubMed  CAS  Google Scholar 

  32. Mittman S, Taylor WR, Copenhagen DR (1990) Concomitant activation of two types of glutamate receptor mediates excitation of salamander retinal ganglion cells. J Physiol 428:175–197

    PubMed  CAS  Google Scholar 

  33. Matsui K, Hosoi N, Tachibana M (1998) Excitatory synaptic transmission in the inner retina: paired recordings of bipolar cells and neurons of the ganglion cell layer. J Neurosci 18:4500–4510

    PubMed  CAS  Google Scholar 

  34. Chen S, Diamond JS (2002) Synaptically released glutamate activates extrasynaptic NMDA receptors on cells in the ganglion cell layer of rat retina. J Neurosci 22:2165–2173

    PubMed  CAS  Google Scholar 

  35. Sagdullaev BT, McCall MA, Lukasiewicz PD (2006) Presynaptic inhibition modulates spillover, creating distinct dynamic response ranges of sensory output. Neuron 50:923–935

    Article  PubMed  CAS  Google Scholar 

  36. Carmignoto G, Vicini S (1992) Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. Science 258:1007–1011

    Article  PubMed  CAS  Google Scholar 

  37. Sheng M, Cummings J, Rolden LA et al (1994) Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature 368:144–147

    Article  PubMed  CAS  Google Scholar 

  38. Quinlan EM, Olstein DH, Bear MF (1999) Bidirectional, experience-dependent regulation of NMDA receptor subunit composition in the rat visual cortex during postnatal development. Proc Natl Acad Sci 96:12876–12880

    Article  PubMed  CAS  Google Scholar 

  39. Nase G, Weishaupt J, Stern P et al (1999) Genetic and epigenetic regulation of NMDA receptor expression in the rat visual cortex. Eur J Neurosci 11:4320–4326

    Article  PubMed  CAS  Google Scholar 

  40. Yashiro K, Philpot BD (2008) Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity. Neuropharmacology 55:1081–1094

    Article  PubMed  CAS  Google Scholar 

  41. Guenther E, Schmid S, Wheeler-Schilling T et al (2004) Developmental plasticity of NMDA receptor function in the retina and the influence of light. FASEB J 18:1433–1435

    PubMed  CAS  Google Scholar 

  42. Xue J, Cooper NG (2001) The modification of NMDA receptors by visual experience in the rat retina is age dependent. Brain Res Mol Brain Res 91:196–203

    Article  PubMed  CAS  Google Scholar 

  43. Giannakopoulos M, Kouvelas ED, Mitsacos A (2010) Experience-dependent regulation of NMDA receptor subunit composition and phosphorylation in the retina and visual cortex. Invest Opthalmol Vis Sci 51:1817–1822

    Article  Google Scholar 

  44. Tian N, Copenhagen DR (2001) Visual deprivation alters development of synaptic function in inner retina after eye opening. Neuron 32:439–449

    Article  PubMed  CAS  Google Scholar 

  45. Tian N, Copenhagen DR (2003) Visual stimulation is required for refinement of ON and OFF pathways in postnatal retina. Neuron 39:85–96

    Article  PubMed  CAS  Google Scholar 

  46. Zhang J, Diamond JS (2006) Distinct perisynaptic and synaptic localization of NMDA and AMPA receptors on ganglion cells in rat retina. J Comp Neurol 498:810–820

    Article  PubMed  CAS  Google Scholar 

  47. Kalbaugh TL, Zhang J, Diamond JS (2009) Coagonist release modulates NMDA receptor subtype contributions at synaptic inputs to retinal ganglion cells. J Neurosci 29:1469–1479

    Article  PubMed  CAS  Google Scholar 

  48. Zhang J, Diamond JS (2009) Subunit and pathway-specific localization of NMDA receptors and scaffolding proteins at ganglion cell synapses in rat retina. J Neurosci 29:4274–4286

    Article  PubMed  CAS  Google Scholar 

  49. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  50. Vecino E, Hernandez M, Garcia M (2004) Cell death in the developing retina. Int J Devol Biol 48:965–974

    Article  CAS  Google Scholar 

  51. Scheetz AJ, Constantine-Paton M (1994) Modulation of NMDA receptor function: implications for vertebrate neural development. FASEB J 8:745–752

    PubMed  CAS  Google Scholar 

  52. Flint AC, Maisch US, Weishaupt JH et al (1997) NR2A subunit expression shortens NMDA receptor synaptic currents in developing neocortex. J Neurosci 17:2469–2476

    PubMed  CAS  Google Scholar 

  53. Rumbaugh G, Prybylowski K, Wang JF et al (2000) Exon 5 and spermine regulate deactivation of NMDA receptor subtypes. J Neurophysiol 83:1300–1306

    PubMed  CAS  Google Scholar 

  54. Lee E-J, Gibo TL, Grzywacz NM (2006) Dark-rearing-induced reduction of GABA and GAD and prevention of the effect by BDNF in the mouse retina. Eur J Neurosci 24:2118–2134

    Article  PubMed  Google Scholar 

  55. Xu H-P, Tian N (2007) Retinal ganglion cell dendrites undergo a visual activity-dependent redistribution after eye opening. J Comp Neurol 503:244–259

    Article  PubMed  Google Scholar 

  56. Bisti S, Gargini C, Chalupa LM (1998) Blokade of glutamate- mediated activity in the developing retina perturbs the functional segregation of ON and OFF pathways. J Neurosci 18:5019–5025

    PubMed  CAS  Google Scholar 

  57. Bodnarenko SR, Chalupa LM (1993) Stratification of ON and OFF ganglion cell dendrites depends on glutamate- mediated afferent activity in the developing retina. Nature 364:144–146

    Article  PubMed  CAS  Google Scholar 

  58. Bodnarenko SR, Jeyarasasingam G, Chalupa LM (1995) Development and regulation of dendritic stratification in retinal ganglion cells by glutamate-mediated afferent activity. J Neurosci 15:7037–7045

    PubMed  CAS  Google Scholar 

  59. Wong WT, Faulkner-Jones BE, Sanes JR et al (2000) Rapid dendritic remodelling in the developing retina: dependence on neurotransmission and reciprocal regulation by Rac and Rho. J Neurosci 20:5024–5036

    PubMed  CAS  Google Scholar 

  60. Scott DB, Blanpied TA, Swanson GT et al (2001) An NMDA ER retention signal regulated by phosphorylation and alternative splicing. J Neurosci 21:3063–3072

    PubMed  CAS  Google Scholar 

  61. Mu Y, Otsuka T, Horton AC et al (2003) Activity-dependent mRNA splicing controls export and synaptic delivery of NMDA receptors. Neuron 40:581–594

    Article  PubMed  CAS  Google Scholar 

  62. Xie J, Black DL (2001) A CaMK IV responsive RNA element mediates depolarization-induced alternative splicing of ion channels. Nature 410:936–939

    Article  PubMed  CAS  Google Scholar 

  63. Pauly T, Schlicksupp A, Neugebauer R et al (2005) Synaptic targeting of NMDA receptor splice variants is regulated differentially by receptor activity. Neuroscience 131:99–111

    Article  PubMed  CAS  Google Scholar 

  64. An P, Grabowski PJ (2007) Exon silencing by UAGG motifs in response to neuronal excitation. PLoS Biol 5:263–280

    Article  CAS  Google Scholar 

  65. Lee JA, Xing Y, Nguyen D et al (2007) Depolarization and CaM kinase IV modulate NMDA receptor splicing through two essential RNA elements. PLoS Biol 5:e40

    Article  PubMed  Google Scholar 

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Acknowledgments

Supported by the K. Kartheodoris Program of the University of Patras and Polembros Shipping Limited.

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, University of Patras, 26500, Patras, Greece

    Georgia Manta, Stavros Taraviras, Elias D. Kouvelas & Adamantia Mitsacos

  2. Biomedical Research Foundation, Academy of Athens, 4 Soranou Efessiou, 11527, Athens, Greece

    Athanasios D. Spathis

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  1. Georgia Manta
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  2. Athanasios D. Spathis
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  4. Elias D. Kouvelas
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Correspondence to Adamantia Mitsacos.

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Manta, G., Spathis, A.D., Taraviras, S. et al. Age and Visual Experience-dependent Expression of NMDAR1 Splice Variants in Rat Retina. Neurochem Res 36, 1417–1425 (2011). https://doi.org/10.1007/s11064-011-0467-5

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