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An NCAM Mimetic, FGL, Alters Hippocampal Cellular Morphometry in Young Adult (4 Month-Old) Rats

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Abstract

The neural cell adhesion molecule, NCAM, is ubiquitously expressed within the CNS and has roles in development, cognition, neural plasticity and regulation of the immune system. NCAM is thus potentially an important pharmacological target for treatment of brain diseases. A cell adhesion mimetic FGL, a 15 amino-acid peptide derived from the second fibronectin type-III module of NCAM, has been shown to act as a neuroprotective agent in experimental disease and ageing models, restoring hippocampal/cognitive function and markedly alleviating deleterious changes in the CNS. However, the effects of FGL on the hippocampus of young healthy rats are unknown. The present study has examined the cellular neurobiological consequences of subcutaneous injections of FGL, on hippocampal cell morphometry in young (4 month-old) rats. We determined the effects of FGL on hippocampal volume, pyramidal neuron number/density (using unbiased quantitative stereology), and examined aspects of neurogenesis (using 2D morphometric analyses). FGL treatment reduced total volume of the dorsal hippocampus (associated with a decrease in total pyramidal neuron numbers in CA1 and CA3), and elevated the number of doublecortin immunolabeled neurons in the dentate gyrus, indicating a likely influence on neurogenesis in young healthy rats. These data indicate that FGL has a specific age dependent effect on the hippocampus, differing according to the development and maturity of the CNS.

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References

  1. Berezin V, Bock E, Poulsen F (2000) The neural cell adhesion molecule NCAM. Curr Opin Drug Discov Dev 3:605–609

    CAS  Google Scholar 

  2. Cavallaro S, D’Agata V, Manickam P, Dufour F, Alkon DL (2002) Memory-specific temporal profiles of gene expression in the hippocampus. Proc Natl Acad Sci USA 99:16279–16284

    Article  PubMed  CAS  Google Scholar 

  3. Cremer H, Lange R, Christoph A, Plomann M, Vopper G, Roes J, Brown R, Baldwin S, Kraemer P, Scheff S, Barthels D, Rajewsky K, Wille W (1994) Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning. Nature 367:455–459

    Article  PubMed  CAS  Google Scholar 

  4. Crossin KL, Krushel LA (2000) Cellular signaling by neural cell adhesion molecules of the immunoglobulin superfamily. Dev Dyn 218:260–279

    Article  PubMed  CAS  Google Scholar 

  5. Luthl A, Laurent JP, Figurov A, Muller D, Schachner M (1994) Hippocampal long-term potentiation and neural cell adhesion molecules L1 and NCAM. Nature 372:777–779

    Article  PubMed  CAS  Google Scholar 

  6. Neiiendam JL, Kohler LB, Christensen C, Li S, Pedersen MV, Ditlevsen DK, Kornum MK, Kiselyov VV, Berezin V, Bock E (2004) An NCAM-derived FGF-receptor agonist, the FGL-peptide, induces neurite outgrowth and neuronal survival in primary rat neurons. J Neurochem 91:920–935

    Article  PubMed  CAS  Google Scholar 

  7. Berezin V, Bock E (2004) NCAM mimetic peptides: pharmacological and therapeutic potential. J Mol Neurosci 22:33–39

    Article  PubMed  Google Scholar 

  8. Kiselyov VV, Skladchikova G, Hinsby AM, Jensen PH, Kulahin N, Soroka V, Pedersen N, Tsetlin V, Poulsen FM, Berezin V, Bock E (2003) Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP. Structure 11:691–701

    Article  PubMed  CAS  Google Scholar 

  9. Walmod PS, Kolkova K, Berezin V, Bock E (2004) Zippers make signals: NCAM mediated molecular interactions and signal transduction. Neurochem Res 29:2015–2035

    Article  PubMed  CAS  Google Scholar 

  10. Berezin V, Bock E (2010) NCAM mimetic peptides: an update. Adv Exp Med Biol 663:337–353

    Article  PubMed  CAS  Google Scholar 

  11. Hansen SM, Li S, Bock E, Berezin V (2010) Synthetic NCAM-derived ligands of the fibroblast growth factor receptor. Adv Exp Med Biol 663:355–372

    Article  PubMed  CAS  Google Scholar 

  12. Cambon K, Hansen SM, Venero C, Herrero AI, Skibo G, Berezin V, Bock E, Sandi C (2004) A synthetic neural cell adhesion molecule mimetic peptide promotes synaptogenesis, enhances presynaptic function, and facilitates memory consolidation. J Neurosci 24:4197–4204

    Article  PubMed  CAS  Google Scholar 

  13. Downer EJ, Cowley TR, Lyons A, Mills KHG, Berezin V, Bock E, Lynch MA (2010) A novel anti-inflammatory role of NCAM-derived mimetic peptide, FGL. Neurobiol Aging 31:118–128

    Article  PubMed  CAS  Google Scholar 

  14. Klementiev B, Novikova T, Novitskaya V, Walmod PS, Dmytriyeva O, Pakkenberg B, Berezin V, Bock E (2007) A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25-35. Neuroscience 145:209–224

    Article  PubMed  CAS  Google Scholar 

  15. Popov VI, Medvedev NI, Kraev IV, Gabbott PL, Davies HA, Lynch M, Cowley TR, Berezin V, Bock E, Stewart MG (2008) A cell adhesion molecule mimetic, FGL peptide, induces alterations in synapse and dendritic spine structure in the dentate gyrus of aged rats: a three-dimensional ultrastructural study. Eur J Neurosci 27:301–314

    Article  PubMed  Google Scholar 

  16. Skibo GG, Lushnikova IV, Voronin KY, Dmitrieva O, Novikova T, Klementiev B, Vaudano E, Berezin VA, Bock E (2005) A synthetic NCAM-derived peptide, FGL, protects hippocampal neurons from ischemic insult both in vitro and in vivo. Eur J Neurosci 22:1589–1596

    Article  PubMed  Google Scholar 

  17. Stewart M, Popov V, Medvedev N, Gabbott P, Corbett N, Kraev I, Davies H (2010) Dendritic spine and synapse morphological alterations induced by a neural cell adhesion molecule (NCAM) mimetic. Adv Exp Med Biol 663:373–383

    Article  PubMed  CAS  Google Scholar 

  18. Ojo B, Rezaie P, Gabbott PL, Colyer F, Medvedev N, Cowley TR, Lynch M, Stewart M (2011) A neural cell adhesion molecule-derived peptide, FGL, attenuates glial cell activation in the aged hippocampus. Exp Neurol 232:318–328

    Article  PubMed  CAS  Google Scholar 

  19. Ojo B, Rezaie P, Gabbott PL, Davies H, Colyer F, Medvedev N, Cowley TR, Lynch M, Stewart M (2011) Age-related changes in the hippocampus (loss of synaptophysin and glial-synaptic interaction) are modified by systemic treatment with an NCAM-derived peptide, FGL. Brain Behav Immun 26:778–788

    Article  PubMed  Google Scholar 

  20. Borcel E, Perez-Alvarez L, Herrero AI, Brionne T, Varea E, Berezin V, Bock E, Sandi C, Venero C (2008) Chronic stress in adulthood followed by intermittent stress impairs spatial memory and the survival of newborn hippocampal cells in ageing animals: prevention by FGL, a peptide mimetic of neural cell adhesion molecule. Behav Pharmacol 19:41–49

    Article  PubMed  Google Scholar 

  21. Jung MW, Weiner SI, McNaughton BL (1994) Comparison of spatial firing characteristics of units in dorsal and ventral hippocampus of the rat. J Neurosci 14:7347–7356

    PubMed  CAS  Google Scholar 

  22. Moser MB, Moser EI, Forrest E, Anderson P, Morris RGM (1995) Spatial learning with minislab in the dorsal hippocampus. Proc Natl Acad Sci USA 92:9697–9701

    Article  PubMed  CAS  Google Scholar 

  23. Secher T, Novitskaia V, Berezin V, Bock E, Glenthoj B, Klementiev B (2006) A neural cell adhesion molecule-derived fibroblast growth factor receptor agonist, the FGL-peptide, promotes early postnatal sensorimotor development and enhances social memory retention. Neuroscience 141:1289–1299

    Article  PubMed  CAS  Google Scholar 

  24. Paxinos G, Watson C (2007) The rat brain in stereotactic co-ordinates, 6th edn. Academic Press, London

    Google Scholar 

  25. Pakkenberg B, Gundersen HJ (1997) Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 384:312–320

    Article  PubMed  CAS  Google Scholar 

  26. Popov VI, Davies HA, Rogachevskii VV, Errington ML, Gabbott PLA, Bliss TVP, Stewart MG (2004) Remodelling of synaptic morphology but unchanged synaptic density during late phase LTP: a serial section EM study of the dentate gyrus in the anaesthetised rat. Neuroscience 28:251–262

    Article  Google Scholar 

  27. Stewart MG, Davies HA, Sandi C, Kraev IV, Rogachevsky VV, Rodriguez JJ, Cordero IM, Donohue HS, Gabbott PLA, Peddie CJ, Popov VI (2005) Stress suppresses and learning induces expression of ultrastructural plasticity in CA3 of rat hippocampus: a 3dimensional ultrastructural study of thorny excrescences and their post synaptic densities. Neuroscience 131:43–54

    Article  PubMed  CAS  Google Scholar 

  28. Gundersen HJ, Jensen EB (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147:229–263

    Article  PubMed  CAS  Google Scholar 

  29. West M, Slomianka JL, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497

    Article  PubMed  CAS  Google Scholar 

  30. Howard CV, Reed MG (1998) Unbiased stereology. Three-dimensional measurement in microscopy. Microscopy handbooks, vol 41. Royal microscopical society. BIOS Scientific Publishers Ltd., Oxford

  31. West MJ (1993) New stereological methods for counting neurons. Neurobiol Ageing 14:275–285

    Article  CAS  Google Scholar 

  32. West MJ (1993) Regionally specific loss of neurons in the ageing human hippocampus. Neurobiol Ageing 14:287–293

    Article  CAS  Google Scholar 

  33. Rapp PR, Gallagher M (1996) Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc Natl Acad Sci USA 93:9926–99230

    Article  PubMed  CAS  Google Scholar 

  34. Mihalick SM, Crandall JE, Langlois JC, Krienke JD, Dube WV (2001) Prenatal ethanol exposure, generalized learning impairment, and medial prefrontal cortical deficits in rats. Neurotoxicol Teratol 23:453–462

    Article  PubMed  CAS  Google Scholar 

  35. Kraev IV, Godukhin OV, Patrushev IV, Davies HA, Popov VI, Stewart MG (2009) Partial kindling induces neurogenesis, activates astrocytes and alters synaptic morphology in the dentate gyrus of freely moving adult rats. Neuroscience 162:254–267

    Article  PubMed  CAS  Google Scholar 

  36. Stadelmann C, Lassmann H (2000) Detection of apoptosis in tissue sections. Cell Tissue Res 301:19–31

    Article  PubMed  CAS  Google Scholar 

  37. Rasmussen T, Schliemann T, Sorensen JC, Zimmer J, West MJ (1996) Memory impaired aged rats: no loss of principal hippocampal and subicular neurons. Neurobiol Ageing 17:143–147

    Article  CAS  Google Scholar 

  38. Chadashvili T, Peterson DA (2006) Cytoarchitecture of fibroblast growth factor receptor 2 (FGFR-2) immunoreactivity in astrocytes of neurogenic and non-neurogenic regions of the young adult and aged rat brain. J Comp Neurol 498:1–15

    Article  PubMed  CAS  Google Scholar 

  39. Brown JP, Couillard-Després S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG (2003) Transient expression of doublecortin during adult neurogenesis. J Comp Neurol 467:1–10

    Article  PubMed  CAS  Google Scholar 

  40. Gleeson JG, Lin PT, Flanagan LA, Walsh CA (1999) Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23:257–2571

    Article  PubMed  CAS  Google Scholar 

  41. Berg MJ, Schifitto G, Powers JM, Martinez-Capolino C, Fong CT, Myers GJ, Epstein LG, Walsh CA (1998) X-linked 1 (Novagen, Madison, WI) vector and protein produced in BL21 E. coli (Stratagene), according to the Manu female band heterotopia–male lissencephaly syndrome. Neurology 50:1143–1146

    Article  PubMed  CAS  Google Scholar 

  42. Stachowiak EK, Roy I, Lee YW, Capacchietti M, Aletta JM, Prasad PN, Stachowiak MK (2009) Targeting novel integrative nuclear FGFR1 signaling by nanoparticle-mediated gene transfer stimulates neurogenesis in the adult brain. Integr Biol (Camb) 1:394–403

    Article  CAS  Google Scholar 

  43. Yoshimura S, Takagi Y, Harada J, Teramoto T, Thomas SS, Waeber C, Bakowska JC, Breakefield XO, Moskowitz MA (2001) FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc Natl Acad Sci USA 98:5874–5879

    Article  PubMed  CAS  Google Scholar 

  44. Jin K, Sun Y, Xie L, Batteur S, Mao XO, Smelick C, Logvinova A, Greenberg DA (2003) Neurogenesis and ageing: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice. Ageing Cell 2:175–183

    Article  CAS  Google Scholar 

  45. Rai KS, Hattiangady B, Shetty AK (2007) Enhanced production and dendritic growth of new dentate granule cells in the middle-aged hippocampus following intracerebroventricular FGF-2 infusions. Eur J Neurosci 26:1765–1779

    Article  PubMed  Google Scholar 

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Acknowledgments

Supported by the European Union FPVI “Promemoria” programme grant (Contract No. 512012) and FP7 ‘MemStick’ (Ref: 201600) and BBSRC grant No. BB/1020330/1.

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Authors and Affiliations

  1. Department of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK

    Bunmi Ojo, Paul L. Gabbott, Payam Rezaie, Nicola Corbett, Nikolay I. Medvedev & Michael G. Stewart

  2. Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland

    Thelma R. Cowley & Marina A. Lynch

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  1. Bunmi Ojo
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  2. Paul L. Gabbott
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  6. Thelma R. Cowley
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  7. Marina A. Lynch
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  8. Michael G. Stewart
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Correspondence to Michael G. Stewart.

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Special Issue: Elisabeth Bock.

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Ojo, B., Gabbott, P.L., Rezaie, P. et al. An NCAM Mimetic, FGL, Alters Hippocampal Cellular Morphometry in Young Adult (4 Month-Old) Rats. Neurochem Res 38, 1208–1218 (2013). https://doi.org/10.1007/s11064-012-0908-9

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  • DOI: https://doi.org/10.1007/s11064-012-0908-9

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