Experimental Brain Research

, Volume 217, Issue 3–4, pp 441–447 | Cite as

Functional consequences of the lack of amyloid precursor protein in the mouse dentate gyrus in vivo

  • Peter Jedlicka
  • Mirka Owen
  • Matej Vnencak
  • Jakob-A. Tschäpe
  • Meike Hick
  • Ulrike C. Müller
  • Thomas Deller
Research Article

Abstract

The amyloid precursor protein (APP) plays a crucial role in the pathogenesis of Alzheimer’s disease. Here, we studied whether the lack of APP affects the synaptic properties in the dentate gyrus by measuring granule cell field potentials evoked by perforant path stimulation in anesthetized 9–11-month-old APP-deficient mice in vivo. We found decreased paired-pulse facilitation, indicating altered presynaptic short-term plasticity in the APP-deficient dentate gyrus. In contrast, excitatory synaptic strength and granule cell firing were unchanged in APP knockout mice. Likewise, long-term potentiation (LTP) induced by a theta-burst stimulation protocol was not impaired in the absence of APP. These findings suggest that the deletion of APP may affect presynaptic plasticity of synaptic transmission at the perforant path–granule cell synapse but leaves synaptic efficacy intact and LTP preserved, possibly due to functional redundancy within the APP gene family.

Keywords

Alzheimer’s disease Synaptic plasticity Granule cell Long-term potentiation Perforant path 

References

  1. Andersen P, Bliss TV, Skrede KK (1971) Unit analysis of hippocampal population spikes. Exp Brain Res 13:208–221PubMedGoogle Scholar
  2. Anliker B, Muller U (2006) The functions of mammalian amyloid precursor protein and related amyloid precursor-like proteins. Neurodegener Dis 3:239–246PubMedCrossRefGoogle Scholar
  3. Bronzino JD, Abu-Hasaballah K, Austin-LaFrance RJ, Morgane PJ (1994) Maturation of long-term potentiation in the hippocampal dentate gyrus of the freely moving rat. Hippocampus 4:439–446PubMedCrossRefGoogle Scholar
  4. Buxbaum JD, Thinakaran G, Koliatsos V, O’Callahan J, Slunt HH, Price DL, Sisodia SS (1998) Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path. J Neurosci 18:9629–9637PubMedGoogle Scholar
  5. Chauvet GA, Berger TW (2002) Hierarchical model of the population dynamics of hippocampal dentate granule cells. Hippocampus 12:698–712PubMedCrossRefGoogle Scholar
  6. Cooke SF, Wu JQ, Plattner F, Errington M, Rowan M, Peters M, Hirano A, Bradshaw KD, Anwyl R, Bliss TVP, Giese KP (2006) Autophosphorylation of alpha CaMKII is not a general requirement for NMDA receptor-dependent LTP in the adult mouse. J Physiol Lond 574:805–818PubMedCrossRefGoogle Scholar
  7. Dawson GR, Seabrook GR, Zheng H, Smith DW, Graham S, O’Dowd G, Bowery BJ, Boyce S, Trumbauer ME, Chen HY, van der Ploeg LH, Sirinathsinghji DJ (1999) Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the beta-amyloid precursor protein. Neuroscience 90:1–13PubMedCrossRefGoogle Scholar
  8. Eckert MJ, Abraham WC (2010) Physiological effects of enriched environment exposure and LTP induction in the hippocampus in vivo do not transfer faithfully to in vitro slices. Learn Mem 17:480–484PubMedCrossRefGoogle Scholar
  9. Eckert MJ, Bilkey DK, Abraham WC (2010) Altered plasticity in hippocampal CA1, but not dentate gyrus, following long-term environmental enrichment. J Neurophysiol 103:3320–3329PubMedCrossRefGoogle Scholar
  10. Fitzjohn SM, Morton RA, Kuenzi F, Davies CH, Seabrook GR, Collingridge GL (2000) Similar levels of long-term potentiation in amyloid precursor protein -null and wild-type mice in the CA1 region of picrotoxin treated slices. Neurosci Lett 288:9–12PubMedCrossRefGoogle Scholar
  11. Furukawa K, Barger SW, Blalock EM, Mattson MP (1996) Activation of K+ channels and suppression of neuronal activity by secreted beta-amyloid-precursor protein. Nature 379:74–78PubMedCrossRefGoogle Scholar
  12. Haass C (2004) Take five–BACE and the gamma-secretase quartet conduct Alzheimer’s amyloid beta-peptide generation. EMBO J 23:483–488PubMedCrossRefGoogle Scholar
  13. Heber S, Herms J, Gajic V, Hainfellner J, Aguzzi A, Rulicke T, von Kooch C, Sisodia S, Tremml P, Lipp HP, Wolfer DP, Muller U (2000) Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J Neurosci 20:7951–7963PubMedGoogle Scholar
  14. Hoe HS, Fu Z, Makarova A, Lee JY, Lu C, Feng L, Pajoohesh-Ganji A, Matsuoka Y, Hyman BT, Ehlers MD, Vicini S, Pak DT, Rebeck GW (2009) The effects of amyloid precursor protein on postsynaptic composition and activity. J Biol Chem 284:8495–8506PubMedCrossRefGoogle Scholar
  15. Jedlicka P, Schwarzacher SW, Winkels R, Kienzler F, Frotscher M, Bramham CR, Schultz C, Bas OC, Deller T (2009a) Impairment of in vivo theta-burst long-term potentiation and network excitability in the dentate gyrus of synaptopodin-deficient mice lacking the spine apparatus and the cisternal organelle. Hippocampus 19:130–140PubMedCrossRefGoogle Scholar
  16. Jedlicka P, Papadopoulos T, Deller T, Betz H, Schwarzacher SW (2009b) Increased network excitability and impaired induction of long-term potentiation in the dentate gyrus of collybistin-deficient mice in vivo. Mol Cell Neurosci 41:94–100PubMedCrossRefGoogle Scholar
  17. Jedlicka P, Hoon M, Papadopoulos T, Vlachos A, Winkels R, Poulopoulos A, Betz H, Deller T, Brose N, Varoqueaux F, Schwarzacher SW (2011) Increased dentate gyrus excitability in neuroligin-2-deficient mice in vivo. Cereb Cortex 21:357–367PubMedCrossRefGoogle Scholar
  18. Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL (1990) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci USA 87:1561–1565PubMedCrossRefGoogle Scholar
  19. Lazarov O, Lee M, Peterson DA, Sisodia SS (2002) Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci 22:9785–9793PubMedGoogle Scholar
  20. Li ZW, Stark G, Gotz J, Rulicke T, Gschwind M, Huber G, Muller U, Weissmann C (1996) Generation of mice with a 200-kb amyloid precursor protein gene deletion by Cre recombinase-mediated site-specific recombination in embryonic stem cells. Proc Natl Acad Sci USA 93:6158–6162PubMedCrossRefGoogle Scholar
  21. Mallm JP, Tschäpe JA, Hick M, Filippov MA, Müller UC (2010) Generation of Conditional Null Alleles for APP and APLP2. Genesis 48:200­–206 Google Scholar
  22. Marquez-Sterling NR, Lo AC, Sisodia SS, Koo EH (1997) Trafficking of cell-surface beta-amyloid precursor protein: evidence that a sorting intermediate participates in synaptic vesicle recycling. J Neurosci 17:140–151PubMedGoogle Scholar
  23. Matthies H, Schroeder H, Becker A, Loh H, Hollt V, Krug M (2000) Lack of expression of long-term potentiation in the dentate gyrus but not in the CA1 region of the hippocampus of mu-opioid receptor-deficient mice. Neuropharmacology 39:952–960PubMedCrossRefGoogle Scholar
  24. Muller U, Cristina N, Li ZW, Wolfer DP, Lipp HP, Rulicke T, Brandner S, Aguzzi A, Weissmann C (1994) Behavioral and anatomical deficits in mice homozygous for a modified beta-amyloid precursor protein gene. Cell 79:755–765PubMedCrossRefGoogle Scholar
  25. NostenBertrand M, Errington ML, Murphy KPSJ, Tokugawa Y, Barboni E, Kozlova E, Michalovich D, Morris RGM, Silver J, Stewart CL, Bliss TVP, Morris RJ (1996) Normal spatial learning despite regional inhibition of LTP in mice lacking Thy-1. Nature 379:826–829CrossRefGoogle Scholar
  26. O’Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34:185–204PubMedCrossRefGoogle Scholar
  27. Phinney AL, Calhoun ME, Wolfer DP, Lipp HP, Zheng H, Jucker M (1999) No hippocampal neuron or synaptic bouton loss in learning-impaired aged beta-amyloid precursor protein-null mice. Neuroscience 90:1207–1216PubMedCrossRefGoogle Scholar
  28. Reinhard C, Hebert SS, De SB (2005) The amyloid-beta precursor protein: integrating structure with biological function. EMBO J 24:3996–4006PubMedCrossRefGoogle Scholar
  29. Ring S, Weyer SW, Kilian SB, Waldron E, Pietrzik CU, Filippov MA, Herms J, Buchholz C, Eckman CB, Korte M, Wolfer DP, Muller UC (2007) The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J Neurosci 27:7817–7826PubMedCrossRefGoogle Scholar
  30. Santos SF, Pierrot N, Morel N, Gailly P, Sindic C, Octave JN (2009) Expression of human amyloid precursor protein in rat cortical neurons inhibits calcium oscillations. J Neurosci 29:4708–4718PubMedCrossRefGoogle Scholar
  31. Seabrook GR, Smith DW, Bowery BJ, Easter A, Reynolds T, Fitzjohn SM, Morton RA, Zheng H, Dawson GR, Sirinathsinghji DJ, Davies CH, Collingridge GL, Hill RG (1999) Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38:349–359PubMedCrossRefGoogle Scholar
  32. Senechal Y, Larmet Y, Dev KK (2006) Unraveling in vivo functions of amyloid precursor protein: insights from knockout and knockdown studies. Neurodegener Dis 3:134–147PubMedCrossRefGoogle Scholar
  33. Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL (1993) Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. J Neurosci 13:3136–3142 Google Scholar
  34. Taylor CJ, Ireland DR, Ballagh I, Bourne K, Marechal NM, Turner PR, Bilkey DK, Tate WP, Abraham WC (2008) Endogenous secreted amyloid precursor protein-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory. Neurobiol Dis 31:250–260PubMedCrossRefGoogle Scholar
  35. Thomson AM (2000) Molecular frequency filters at central synapses. Prog Neurobiol 62:159–196PubMedCrossRefGoogle Scholar
  36. Turner PR, O’Connor K, Tate WP, Abraham WC (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 70:1–32PubMedCrossRefGoogle Scholar
  37. von Koch CS, Zheng H, Chen H, Trumbauer M, Thinakaran G, van der Ploeg LH, Price DL, Sisodia SS (1997) Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice. Neurobiol Aging 18:661–669CrossRefGoogle Scholar
  38. Wang P, Yang G, Mosier DR, Chang P, Zaidi T, Gong YD, Zhao NM, Dominguez B, Lee KF, Gan WB, Zheng H (2005) Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. J Neurosci 25:1219–1225PubMedCrossRefGoogle Scholar
  39. Wang B, Yang L, Wang Z, Zheng H (2007) Amyloid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter. Proc Natl Acad Sci USA 104:14140–14145PubMedCrossRefGoogle Scholar
  40. Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, Zheng H (2009) Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J Neurosci 29:10788–10801PubMedCrossRefGoogle Scholar
  41. Weyer SW, Klevanski M, Delekate A, Voikar V, Aydin D, Hick M, Filippov M, Drost N, Schaller KL, Saar M, Vogt MA, Gass P, Samanta A, Jaschke A, Korte M, Wolfer DP, Caldwell JH, Muller UC (2011) APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP. EMBO J 30:2266–2280PubMedCrossRefGoogle Scholar
  42. Winkels R, Jedlicka P, Weise FK, Schultz C, Deller T, Schwarzacher SW (2009) Reduced excitability in the dentate gyrus network of betaIV-spectrin mutant mice in vivo. Hippocampus 19:677–686PubMedCrossRefGoogle Scholar
  43. Wu CC, Chawla F, Games D, Rydel RE, Freedman S, Schenk D, Young WG, Morrison JH, Bloom FE (2004) Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: digital morphometric analyses. Proc Natl Acad Sci USA 101:7141–7146PubMedCrossRefGoogle Scholar
  44. Yamazaki T, Selkoe DJ, Koo EH (1995) Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons. J Cell Biol 129:431–442PubMedCrossRefGoogle Scholar
  45. Yang L, Wang Z, Wang B, Justice NJ, Zheng H (2009) Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity. J Neurosci 29:15660–15668PubMedCrossRefGoogle Scholar
  46. Yun SH, Gamkrelidze G, Stine WB, Sullivan PM, Pasternak JF, Ladu MJ, Trommer BL (2006) Amyloid-beta1-42 reduces neuronal excitability in mouse dentate gyrus. Neurosci Lett 403:162–165PubMedCrossRefGoogle Scholar
  47. Zheng H, Koo EH (2006) The amyloid precursor protein: beyond amyloid. Mol Neurodegener 1:5PubMedCrossRefGoogle Scholar
  48. Zheng H, Jiang M, Trumbauer ME, Sirinathsinghji DJ, Hopkins R, Smith DW, Heavens RP, Dawson GR, Boyce S, Conner MW, Stevens KA, Slunt HH, Sisoda SS, Chen HY, van der Ploeg LH (1995) beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81:525–531PubMedCrossRefGoogle Scholar
  49. Zucker RS, Regehr WG (2002) Short-term synaptic plasticity. Annu Rev Physiol 64:355–405PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Peter Jedlicka
    • 1
  • Mirka Owen
    • 1
  • Matej Vnencak
    • 1
  • Jakob-A. Tschäpe
    • 2
  • Meike Hick
    • 2
  • Ulrike C. Müller
    • 2
  • Thomas Deller
    • 1
  1. 1.Institute of Clinical Neuroanatomy, Neuroscience CenterGoethe-UniversityFrankfurt am MainGermany
  2. 2.Institute of Pharmacy and Molecular BiotechnologyHeidelberg UniversityHeidelbergGermany

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