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

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• dc.contributor.author Castro, Patricio A.ca
• dc.contributor.author Ramírez, Alejandra E.ca
• dc.contributor.author Sepúlveda, Fernando J.ca
• dc.contributor.author Peters, Christianca
• dc.contributor.author Fierro, Humbertoca
• dc.contributor.author Waldron, Javierca
• dc.contributor.author Luza, Sandraca
• dc.contributor.author Fuentealba, Jorgeca
• dc.contributor.author Muñoz López, Francisco José, 1964-ca
• dc.contributor.author De Ferrari, Giancarlo V.ca
• dc.contributor.author Bush, Ashley I.ca
• dc.contributor.author Aguayo, Luis G.ca
• dc.contributor.author Opazo, Carlos M.ca
• dc.date.accessioned 2015-06-08T08:49:39Z
• dc.date.available 2015-06-08T08:49:39Z
• dc.date.issued 2014ca
• dc.description.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.en
• dc.description.sponsorship This work was supported by Fundación Andes Fellowship No 14060/77 (Carlos M. Opazo), Ring of Research PBCTACT-04 (Luis G. Aguayo,Giancarlo V. De Ferrari and Carlos M. Opazo),doctoral thesis support grant AT-24080125 (Patricio A. Castro) and DIUC grant No 205.033.101–1.0 (Carlos M. Opazo).en
• dc.format.mimetype application/pdfca
• dc.identifier.citation Castro PA, Ramírez A, Sepúlveda FJ, Peters C, Fierro H, Waldron J 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. 2014;6:319. DOI: 10.3389/fnagi.2014.00319ca
• dc.identifier.doi http://dx.doi.org/10.3389/fnagi.2014.00319
• dc.identifier.issn 1663-4365ca
• dc.identifier.uri http://hdl.handle.net/10230/23755
• dc.language.iso engca
• dc.publisher Frontiersca
• dc.relation.ispartof Frontiers in Aging Neuroscience. 2014;6:319
• dc.rights © 2014 Castro, Ramirez, Sepúlveda, Peters, Fierro, Waldron, Luza, Fuentealba, Muñoz, De Ferrari, Bush, Aguayo and Opazo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these termsca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Copperen
• dc.subject.keyword Zincen
• dc.subject.keyword Neocuproineen
• dc.subject.keyword Synaptic activityen
• dc.subject.keyword Dynaminen
• dc.subject.keyword Synapsinen
• dc.subject.keyword Hyperexcitabilityen
• dc.subject.keyword Epileptiform-like activityen
• dc.subject.other Hipocamp (Cervell)ca
• dc.subject.other Neuronesca
• dc.title Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neuronsen
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca