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

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 Opazo

Resultado de la investigación: Contribución a una revistaArtículo

10 Citas (Scopus)

Resumen

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, 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. 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 Bathocuproine, 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. 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.

Idioma originalInglés
Número de artículo319
PublicaciónFrontiers in Aging Neuroscience
Volumen6
N.ºOCT
DOI
EstadoPublicada - 2014

Áreas temáticas de ASJC Scopus

  • Estudio del envejecimiento
  • Neurociencia cognitiva

Huella Profundice en los temas de investigación de 'Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: Modulation of synaptic activity in hippocampal neurons'. En conjunto forman una huella única.

  • Citar esto

    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. (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, 6(OCT), [319]. https://doi.org/10.3389/fnagi.2014.00319