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Castro PA, Ramirez A, Sepúlveda FJ, et al. Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neurons. Front Aging Neurosci. 2014;6:319doi: 10.3389/fnagi.2014.00319.
Castro, P. A., Ramirez, A., Sepúlveda, F. J., Peters, C., Fierro, H., Waldron, J., Luza, S., Fuentealba, J., Muñoz, F. J., De Ferrari, G. V., Bush, A. I., Aguayo, L. G., & Opazo, C. M. (2014). Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neurons. Frontiers in aging neuroscience, 6319. https://doi.org/10.3389/fnagi.2014.00319
Castro, Patricio A, et al. "Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neurons." Frontiers in aging neuroscience vol. 6 (2014): 319. doi: https://doi.org/10.3389/fnagi.2014.00319
Castro PA, Ramirez A, Sepúlveda FJ, Peters C, Fierro H, Waldron J, Luza S, Fuentealba J, Muñoz FJ, De Ferrari GV, Bush AI, Aguayo LG, Opazo CM. Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neurons. Front Aging Neurosci. 2014 Dec 03;6:319. doi: 10.3389/fnagi.2014.00319. eCollection 2014. PMID: 25520655; PMCID: PMC4253966.
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Front Aging Neurosci. 2014 Dec 03;6:319. doi: 10.3389/fnagi.2014.00319. eCollection 2014.

Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neurons.

Frontiers in aging neuroscience

Patricio A Castro, Alejandra Ramirez, Fernando J Sepúlveda, Christian Peters, Humberto Fierro, Javier Waldron, Sandra Luza, Jorge Fuentealba, Francisco J Muñoz, Giancarlo V De Ferrari, Ashley I Bush, Luis G Aguayo, Carlos M Opazo

Affiliations

  1. Department of Physiology and Membrane Biology, Shriners Hospital for Children Northern California, University of California at Davis School of Medicine California, USA.
  2. Laboratorio de Neurofisiología, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción Concepción, Chile ; Oxidation Biology Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne Parkville, Melbourne, Victoria, Australia.
  3. Laboratorio de Neurofisiología, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción Concepción, Chile.
  4. Oxidation Biology Laboratory, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne Parkville, Melbourne, Victoria, Australia.
  5. Laboratory of Molecular Physiology and Channelopathies, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra Barcelona, Spain.
  6. Center for Biomedical Research and FONDAP Center for Genome Regulation, Universidad Andrés Bello Santiago, Chile.

PMID: 25520655 PMCID: PMC4253966 DOI: 10.3389/fnagi.2014.00319

Abstract

Extracellular and intracellular copper and zinc regulate synaptic activity and plasticity, which may impact brain functionality and human behavior. We have found that a metal coordinating molecule, Neocuproine, transiently increases free intracellular copper and zinc levels (i.e., min) in hippocampal neurons as monitored by Phen Green and FluoZin-3 fluorescence, respectively. The changes in free intracellular zinc induced by Neocuproine were abolished by the presence of a non-permeant copper chelator, Bathocuproine (BC), indicating that copper influx is needed for the action of Neocuproine on intracellular Zn levels. Moreover, Neocuproine decreased the mRNA levels of Synapsin and Dynamin, and did not affect the expression of Bassoon, tubulin or superoxide dismutase (SOD). Western blot analysis showed that protein levels of synapsin and dynamin were also down regulated in the presence of Neocuproine and that these changes were accompanied by a decrease in calcium transients and neuronal activity. Furthermore, Neocuproine decreased the number of active neurons, effect that was blocked by the presence of BC, indicating that copper influx is needed for the action of Neocuproine. We finally show that Neocuproine blocks the epileptiform-like activity induced by bicuculline in hippocampal neurons. Collectively, our data indicates that presynaptic protein configuration and function of primary hippocampal neurons is sensitive to transient changes in transition metal homeostasis. Therefore, small molecules able to coordinate transition metals and penetrate the blood-brain barrier might modify neurotransmission at the Central Nervous System (CNS). This might be useful to establish therapeutic approaches to control the neuronal hyperexcitabiltity observed in brain conditions that are associated to copper dyshomeotasis such as Alzheimer's and Menkes diseases. Our work also opens a new avenue to find novel and effective antiepilepsy drugs based in metal coordinating molecules.

Keywords: copper; dynamin; epileptiform-like activity; hyperexcitability; neocuproine; synapsin; synaptic activity; zinc

References

  1. Comp Biochem Physiol C Toxicol Pharmacol. 2003 Jun;135(2):107-18 - PubMed
  2. J Neurosci. 1994 Nov;14(11 Pt 1):6325-35 - PubMed
  3. Nature. 2014 Jul 10;511(7508):S12-3 - PubMed
  4. Brain. 2014 Jan;137(Pt 1):137-52 - PubMed
  5. Nature. 1983 May 5-11;303(5912):64-5 - PubMed
  6. Anal Bioanal Chem. 2004 Sep;380(2):240-6 - PubMed
  7. Eur J Pharmacol. 2011 Aug 16;664(1-3):36-44 - PubMed
  8. Prog Neurobiol. 2011 Aug;94(3):296-306 - PubMed
  9. Pharmacol Ther. 2006 Sep;111(3):567-83 - PubMed
  10. Mol Cell Biochem. 1993 Sep 8;126(1):17-23 - PubMed
  11. Free Radic Biol Med. 2011 Jul 15;51(2):480-9 - PubMed
  12. J Pharmacol Exp Ther. 2005 Mar;312(3):1138-43 - PubMed
  13. Trends Neurosci. 2003 Apr;26(4):207-14 - PubMed
  14. J Neurosci. 2011 Nov 9;31(45):16076-85 - PubMed
  15. Toxicol Sci. 2008 Mar;102(1):138-49 - PubMed
  16. Free Radic Biol Med. 2012 Jan 15;52(2):298-302 - PubMed
  17. Mol Cell Neurosci. 2009 Aug;41(4):420-8 - PubMed
  18. Front Aging Neurosci. 2014 Jul 03;6:143 - PubMed
  19. J Neurochem. 2007 Mar;100(5):1143-54 - PubMed
  20. J Neurosci Res. 2001 Mar 1;63(5):447-52 - PubMed
  21. Brain Dev. 2011 Nov;33(10 ):866-76 - PubMed
  22. J Neurosci Methods. 2003 Sep 30;128(1-2):159-72 - PubMed
  23. J Neurophysiol. 2014 May;111(10):1927-39 - PubMed
  24. Neuron. 2003 Oct 30;40(3):595-607 - PubMed
  25. J Neurosci Res. 2013 Jan;91(1):2-19 - PubMed
  26. Brain Res. 1996 Dec 2;742(1-2):211-8 - PubMed
  27. Eur J Pharmacol. 2000 Oct 13;406(2):293-300 - PubMed
  28. Brain Res. 2009 Feb 23;1256:69-75 - PubMed
  29. Synapse. 1988;2(4):412-5 - PubMed
  30. J Biol Chem. 2002 Nov 22;277(47):44670-6 - PubMed
  31. Brain Res. 2014 Jan 13;1542:20-31 - PubMed
  32. Int J Clin Exp Pathol. 2008 Jan 01;1(2):157-68 - PubMed
  33. Brain Res. 2005 Sep 21;1056(2):176-82 - PubMed
  34. Eur J Neurosci. 1996 Nov;8(11):2257-64 - PubMed
  35. Neurosci Lett. 1989 Aug 28;103(2):139-44 - PubMed
  36. Neurotox Res. 2012 Jan;21(1):128-41 - PubMed
  37. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9572-7 - PubMed
  38. Ann N Y Acad Sci. 2014 May;1314:15-23 - PubMed
  39. Epilepsia. 2006 May;47(5):867-72 - PubMed
  40. J Neurophysiol. 1996 Oct;76(4):2536-46 - PubMed
  41. J Neurochem. 2011 Oct;119(1):78-88 - PubMed
  42. Brain Res. 1990 Oct 8;529(1-2):16-22 - PubMed

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