Neurochemical Research

, Volume 41, Issue 5, pp 1085–1097 | Cite as

Adenosine A1 Receptor-Mediated Endocytosis of AMPA Receptors Contributes to Impairments in Long-Term Potentiation (LTP) in the Middle-Aged Rat Hippocampus

  • Zhicheng Chen
  • Jocelyn Stockwell
  • Francisco S. Cayabyab
Original Paper
First Online:
Received:
Revised:
Accepted:

Abstract

Aging causes multiple changes in the mammalian brain, including changes in synaptic signaling. Previous reports have shown increased extracellular adenosine in the aging brain, and we recently reported that activation of adenosine A1 receptors (A1Rs) induces AMPA receptor (AMPAR) internalization in rat hippocampus. This study investigated whether aging-related changes in the rat hippocampus include altered surface expression of adenosine A1 and A2A receptors, and whether these changes correspond to changes in AMPAR surface expression and altered synaptic plasticity. We found reduced A1R surface expression in middle-aged rat hippocampus, and also reduced GluA1 and GluA2 AMPAR subunit surface expression. Using a chemically-induced LTP (cLTP) experimental protocol, we recorded fEPSPs in young (1 month old) and middle-aged (7–12 month old) rat hippocampal slices. There were significant impairments in cLTP in middle-aged slices, suggesting impaired synaptic plasticity. Since we previously showed that the A1R agonist N6-cyclopentyladenosine (CPA) reduced both A1Rs and GluA2/GluA1 AMPARs, we hypothesized that the observed impaired synaptic plasticity in middle-aged brains is regulated by A1R-mediated AMPAR internalization by clathrin-mediated endocytosis. Following cLTP, we found a significant increase in GluA1 and GluA2 surface expression in young rats, which was blunted in middle-aged brains or in young brains pretreated with CPA. Blocking A1Rs with 8-cyclopentyl-1,3-dipropylxanthine or AMPAR endocytosis with either Tat-GluA2-3Y peptide or dynasore (dynamin inhibitor) similarly enhanced AMPAR surface expression following cLTP. These data suggest that age-dependent alteration in adenosine receptor expression contributes to increased AMPAR endocytosis and impaired synaptic plasticity in aged brains.

Keywords

Field excitatory postsynaptic potentials (fEPSPs) GluA2-containing AMPA receptors Clathrin-mediated endocytosis Long term potentiation (LTP) Aging 
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Notes

Compliance with Ethical Standards

Conflict of interest

The authors assert that they have no competing financial interests.

References

  1. 1.
    Chen Z, Xiong C, Pancyr C, Stockwell J, Walz W, Cayabyab FS (2014) Prolonged adenosine A1 receptor activation in hypoxia and pial vessel disruption focal cortical ischemia facilitates clathrin-mediated AMPA receptor endocytosis and long-lasting synaptic inhibition in rat hippocampal CA3–CA1 synapses: differential regulation of GluA2 and GluA1 subunits by p38 MAPK and JNK. J Neurosci 34:9621–9643CrossRefPubMedGoogle Scholar
  2. 2.
    Murillo-Rodriguez E, Blanco-Centurion C, Gerashchenko D, Salin-Pascual RJ, Shiromani PJ (2004) The diurnal rhythm of adenosine levels in the basal forebrain of young and old rats. Neuroscience 123:361–370CrossRefPubMedGoogle Scholar
  3. 3.
    Sperlagh B, Zsilla G, Baranyi M, Kekes-Szabo A, Vizi ES (1997) Age-dependent changes of presynaptic neuromodulation via A1-adenosine receptors in rat hippocampal slices. Int J Dev Neurosci 15:739–747CrossRefPubMedGoogle Scholar
  4. 4.
    Sebastiao AM, Cunha RA, de Mendonca A, Ribeiro JA (2000) Modification of adenosine modulation of synaptic transmission in the hippocampus of aged rats. Br J Pharmacol 131:1629–1634CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Jin ZL, Lee TF, Zhou SJ, Wang LC (1993) Age-dependent change in the inhibitory effect of an adenosine agonist on hippocampal acetylcholine release in rats. Brain Res Bull 30:149–152CrossRefPubMedGoogle Scholar
  6. 6.
    Zimmermann H (1996) Biochemistry, localization and functional roles of ecto-nucleotidases in the nervous system. Prog Neurobiol 49:589–618CrossRefPubMedGoogle Scholar
  7. 7.
    Cunha RA, Almeida T, Ribeiro JA (2001) Parallel modification of adenosine extracellular metabolism and modulatory action in the hippocampus of aged rats. J Neurochem 76:372–382CrossRefPubMedGoogle Scholar
  8. 8.
    Ritchie K, Carriere I, De Mendonca A, Portet F, Dartigues JF, Rouaud O, Barberger-Gateau P, Ancelin ML (2007) The neuroprotective effects of caffeine: a prospective population study (the Three City Study). Neurology 69:536–545CrossRefPubMedGoogle Scholar
  9. 9.
    Granger R, Deadwyler S, Davis M, Moskovitz B, Kessler M, Rogers G, Lynch G (1996) Facilitation of glutamate receptors reverses an age-associated memory impairment in rats. Synapse 22:332–337CrossRefPubMedGoogle Scholar
  10. 10.
    Shankar S, Teyler TJ, Robbins N (1998) Aging differentially alters forms of long-term potentiation in rat hippocampal area CA1. J Neurophysiol 79:334–341PubMedGoogle Scholar
  11. 11.
    Deupree DL, Turner DA, Watters CL (1991) Spatial performance correlates with in vitro potentiation in young and aged Fischer 344 rats. Brain Res 554:1–9CrossRefPubMedGoogle Scholar
  12. 12.
    Barnes CA (1979) Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 93:74–104CrossRefPubMedGoogle Scholar
  13. 13.
    Barnes CA, McNaughton BL (1985) An age comparison of the rates of acquisition and forgetting of spatial information in relation to long-term enhancement of hippocampal synapses. Behav Neurosci 99:1040–1048CrossRefPubMedGoogle Scholar
  14. 14.
    Deupree DL, Bradley J, Turner DA (1993) Age-related alterations in potentiation in the CA1 region in F344 rats. Neurobiol Aging 14:249–258CrossRefPubMedGoogle Scholar
  15. 15.
    Oler JA, Markus EJ (1998) Age-related deficits on the radial maze and in fear conditioning: hippocampal processing and consolidation. Hippocampus 8:402–415CrossRefPubMedGoogle Scholar
  16. 16.
    Ward MT, Oler JA, Markus EJ (1999) Hippocampal dysfunction during aging I: deficits in memory consolidation. Neurobiol Aging 20:363–372CrossRefPubMedGoogle Scholar
  17. 17.
    Meneses A, Manuel-Apolinar L, Rocha L, Castillo E, Castillo C (2004) Expression of the 5-HT receptors in rat brain during memory consolidation. Behav Brain Res 152:425–436CrossRefPubMedGoogle Scholar
  18. 18.
    Costenla AR, de Mendonça A, Ribeiro JA (1999) Adenosine modulates synaptic plasticity in hippocampal slices from aged rats. Brain Res 851:228–234CrossRefPubMedGoogle Scholar
  19. 19.
    Ribeiro JA (1995) Purinergic inhibition of neurotransmitter release in the central nervous system. Pharmacol Toxicol 77:299–305CrossRefPubMedGoogle Scholar
  20. 20.
    Lu G, Zhou QX, Kang S, Li QL, Zhao LC, Chen JD, Sun JF, Cao J, Wang YJ, Chen J, Chen XY, Zhong DF, Chi ZQ, Xu L, Liu JG (2010) Chronic morphine treatment impaired hippocampal long-term potentiation and spatial memory via accumulation of extracellular adenosine acting on adenosine A1 receptors. J Neurosci 30:5058–5070CrossRefPubMedGoogle Scholar
  21. 21.
    de Mendonca A, Almeida T, Bashir ZI, Ribeiro JA (1997) Endogenous adenosine attenuates long-term depression and depotentiation in the CA1 region of the rat hippocampus. Neuropharmacology 36:161–167CrossRefPubMedGoogle Scholar
  22. 22.
    de Mendonca A, Ribeiro JA (1994) Endogenous adenosine modulates long-term potentiation in the hippocampus. Neuroscience 62:385–390CrossRefPubMedGoogle Scholar
  23. 23.
    de Mendonca A, Ribeiro JA (2000) Long-term potentiation observed upon blockade of adenosine A1 receptors in rat hippocampus is N-methyl-d-aspartate receptor-dependent. Neurosci Lett 291:81–84CrossRefPubMedGoogle Scholar
  24. 24.
    Otmakhov N, Khibnik L, Otmakhova N, Carpenter S, Riahi S, Asrican B, Lisman J (2004) Forskolin-induced LTP in the CA1 hippocampal region is NMDA receptor dependent. J Neurophysiol 91:1955–1962CrossRefPubMedGoogle Scholar
  25. 25.
    Schapitz IU, Behrend B, Pechmann Y, Lappe-Siefke C, Kneussel SJ, Wallace KE, Stempel AV, Buck F, Grant SG, Schweizer M, Schmitz D, Schwarz JR, Holzbaur EL, Kneussel M (2010) Neuroligin 1 is dynamically exchanged at postsynaptic sites. J Neurosci 30:12733–12744CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kim MJ, Futai K, Jo J, Hayashi Y, Cho K, Sheng M (2007) Synaptic accumulation of PSD-95 and synaptic function regulated by phosphorylation of serine-295 of PSD-95. Neuron 56:488–502CrossRefPubMedGoogle Scholar
  27. 27.
    Oh MC, Derkach VA, Guire ES, Soderling TR (2006) Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation. J Biol Chem 281:752–758CrossRefPubMedGoogle Scholar
  28. 28.
    Zamanillo D, Sprengel R, Hvalby O, Jensen V, Burnashev N, Rozov A, Kaiser KM, Koster HJ, Borchardt T, Worley P, Lubke J, Frotscher M, Kelly PH, Sommer B, Andersen P, Seeburg PH, Sakmann B (1999) Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284:1805–1811CrossRefPubMedGoogle Scholar
  29. 29.
    Costenla AR, Diogenes MJ, Canas PM, Rodrigues RJ, Nogueira C, Maroco J, Agostinho PM, Ribeiro JA, Cunha RA, de Mendonca A (2011) Enhanced role of adenosine A(2A) receptors in the modulation of LTP in the rat hippocampus upon ageing. Eur J Neurosci 34:12–21CrossRefPubMedGoogle Scholar
  30. 30.
    Cunha RA (2005) Neuroprotection by adenosine in the brain: from A1 receptor activation to A2A receptor blockade. Purinergic Signal 1:111–134CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Rodrigues RJ, Canas PM, Lopes LV, Oliveira CR, Cunha RA (2008) Modification of adenosine modulation of acetylcholine release in the hippocampus of aged rats. Neurobiol Aging 29:1597–1601CrossRefPubMedGoogle Scholar
  32. 32.
    Cunha RA, Dolores Constantino M, Fonseca E, Ribeiro JA (2001) Age-dependent decrease in adenosine A1 receptor binding sites in the rat brain: effect of cis unsaturated free fatty acids. Eur J Biochem 268:2939–2947CrossRefPubMedGoogle Scholar
  33. 33.
    Leon D, Albasanz JL, Ruiz MA, Martin M (2005) Chronic caffeine or theophylline intake during pregnancy inhibits A1 receptor function in the rat brain. Neuroscience 131:481–489CrossRefPubMedGoogle Scholar
  34. 34.
    Cunha RA, Constantino MC, Sebastiao AM, Ribeiro JA (1995) Modification of A1 and A2a adenosine receptor binding in aged striatum, hippocampus and cortex of the rat. NeuroReport 6:1583–1588CrossRefPubMedGoogle Scholar
  35. 35.
    Rebola N, Sebastiao AM, de Mendonca A, Oliveira CR, Ribeiro JA, Cunha RA (2003) Enhanced adenosine A2A receptor facilitation of synaptic transmission in the hippocampus of aged rats. J Neurophysiol 90:1295–1303CrossRefPubMedGoogle Scholar
  36. 36.
    Brust TB, Cayabyab FS, MacVicar BA (2007) C-Jun N-terminal kinase regulates adenosine A1 receptor-mediated synaptic depression in the rat hippocampus. Neuropharmacology 53:906–917CrossRefPubMedGoogle Scholar
  37. 37.
    Brust TB, Cayabyab FS, Zhou N, MacVicar BA (2006) p38 mitogen-activated protein kinase contributes to adenosine A1 receptor-mediated synaptic depression in area CA1 of the rat hippocampus. J Neurosci 26:12427–12438CrossRefPubMedGoogle Scholar
  38. 38.
    Ahmadian G, Ju W, Liu L, Wyszynski M, Lee SH, Dunah AW, Taghibiglou C, Wang Y, Lu J, Wong TP, Sheng M, Wang YT (2004) Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD. EMBO J 23:1040–1050CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Rosenzweig ES, Barnes CA (2003) Impact of aging on hippocampal function: plasticity, network dynamics, and cognition. Prog Neurobiol 69:143–179CrossRefPubMedGoogle Scholar
  40. 40.
    Bergado JA, Almaguer W (2002) Aging and synaptic plasticity: a review. Neural Plast 9:217–232CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Dieguez D Jr, Barea-Rodriguez EJ (2004) Aging impairs the late phase of long-term potentiation at the medial perforant path-CA3 synapse in awake rats. Synapse 52:53–61CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Barnes CA, Rao G, Foster TC, McNaughton BL (1992) Region-specific age effects on AMPA sensitivity: electrophysiological evidence for loss of synaptic contacts in hippocampal field CA1. Hippocampus 2:457–468CrossRefPubMedGoogle Scholar
  43. 43.
    Rex CS, Kramar EA, Colgin LL, Lin B, Gall CM, Lynch G (2005) Long-term potentiation is impaired in middle-aged rats: regional specificity and reversal by adenosine receptor antagonists. J Neurosci 25:5956–5966CrossRefPubMedGoogle Scholar
  44. 44.
    Anggono V, Huganir RL (2012) Regulation of AMPA receptor trafficking and synaptic plasticity. Curr Opin Neurobiol 22:461–469CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Malinow R, Malenka RC (2002) AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25:103–126CrossRefPubMedGoogle Scholar
  46. 46.
    Man HY, Lin JW, Ju WH, Ahmadian G, Liu L, Becker LE, Sheng M, Wang YT (2000) Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron 25:649–662CrossRefPubMedGoogle Scholar
  47. 47.
    Nicoll RA, Tomita S, Bredt DS (2006) Auxiliary subunits assist AMPA-type glutamate receptors. Science 311:1253–1256CrossRefPubMedGoogle Scholar
  48. 48.
    Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N, Kuhl D, Huganir RL, Worley PF (2006) Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52:445–459CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Tzingounis AV, Nicoll RA (2006) Arc/Arg3.1: linking gene expression to synaptic plasticity and memory. Neuron 52:403–407CrossRefPubMedGoogle Scholar
  50. 50.
    Shepherd JD, Rumbaugh G, Wu J, Chowdhury S, Plath N, Kuhl D, Huganir RL, Worley PF (2006) Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron 52:475–484CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Liu SJ, Zukin RS (2007) Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci 30:126–134CrossRefPubMedGoogle Scholar
  52. 52.
    Henley JM, Wilkinson KA (2013) AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging. Dialogues Clin Neurosci 15:11–27PubMedPubMedCentralGoogle Scholar
  53. 53.
    Diogenes MJ, Costenla AR, Lopes LV, Jeronimo-Santos A, Sousa VC, Fontinha BM, Ribeiro JA, Sebastiao AM (2011) Enhancement of LTP in aged rats is dependent on endogenous BDNF. Neuropsychopharmacology 36:1823–1836CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Lu KT, Gean PW (1999) Masking of forskolin-induced long-term potentiation by adenosine accumulation in area CA1 of the rat hippocampus. Neuroscience 88:69–78CrossRefPubMedGoogle Scholar
  55. 55.
    Stockwell J, Chen Z, Niazi M, Nosib S, Cayabyab FS (2016) Protein phosphatase role in adenosine A1 receptor-induced AMPA receptor trafficking and rat hippocampal neuronal damage in hypoxia/reperfusion injury. Neuropharmacology 102:254–265. doi: 10.1016/j.neuropharm.2015.11.018 CrossRefPubMedGoogle Scholar
  56. 56.
    Cheng JT, Liu IM, Juang SW, Jou SB (2000) Decrease of adenosine A-1 receptor gene expression in cerebral cortex of aged rats. Neurosci Lett 283:227–229CrossRefPubMedGoogle Scholar
  57. 57.
    Pagonopoulou O, Angelatou F (1992) Reduction of A1 adenosine receptors in cortex, hippocampus and cerebellum in ageing mouse brain. NeuroReport 3:735–737CrossRefPubMedGoogle Scholar
  58. 58.
    Canas PM, Porciuncula LO, Cunha GMA, Silva CG, Machado NJ, Oliveira JMA, Oliveira CR, Cunha RA (2009) Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci 29:14741–14751CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Zhicheng Chen
    • 1
  • Jocelyn Stockwell
    • 2
  • Francisco S. Cayabyab
    • 2
  1. 1.Laboratory for Neurodegenerative ResearchBrigham & Women’s Hospital and Harvard Institutes of MedicineBostonUSA
  2. 2.Department of Surgery, Neuroscience Research Group, College of Medicine, Room GD30.5, D-Wing Health Science BuildingUniversity of SaskatchewanSaskatoonCanada

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