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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2014
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en
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Frontiers Research Foundation
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Atribution 4.0 International (CC BY 4.0)
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https://creativecommons.org/licenses/by/4.0/deed.es
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 (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.
Notas
Indexación: Scopus.
Palabras clave
Copper, Zinc, Neocuproine, Synaptic Activity, Dynamin,, Synapsin, Hyperexcitability, Epileptiform-Like Activity
Citación
Frontiers in Aging Neuroscience. Volume 6, Issue OCT. 2014 Article number 319
DOI
DOI: 10.3389/fnagi.2014.00319