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: Article

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 originalEnglish
Número de artículo319
PublicaciónFrontiers in Aging Neuroscience
Volumen6
N.ºOCT
DOI
EstadoPublished - 2014

Huella dactilar

Synapsins
Dynamins
Copper
Down-Regulation
Neurons
Metals
Zinc
Menkes Kinky Hair Syndrome
Neuronal Plasticity
Bicuculline
neocuproine
Brain
Tubulin
Chelating Agents
Blood-Brain Barrier
Synaptic Transmission
Superoxide Dismutase
Alzheimer Disease
Proteins
Homeostasis

ASJC Scopus subject areas

  • Ageing
  • Cognitive Neuroscience

Citar esto

Castro, Patricio A. ; Ramirez, Alejandra ; Sepúlveda, Fernando J. ; Peters, Christian ; Fierro, Humberto ; Waldron, Javier ; Luza, Sandra ; Fuentealba, Jorge ; Muñoz, Francisco J. ; De Ferrari, Giancarlo V. ; Bush, Ashley I. ; Aguayo, Luis G. ; Opazo, Carlos. / Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine : Modulation of synaptic activity in hippocampal neurons. En: Frontiers in Aging Neuroscience. 2014 ; Vol. 6, N.º OCT.
@article{127625403f1c45a79d1f801f15ac693e,
title = "Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: Modulation of synaptic activity in hippocampal neurons",
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, 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.",
keywords = "Copper, Dynamin, Epileptiform-like activity, Hyperexcitability, Neocuproine, Synapsin, Synaptic activity, Zinc",
author = "Castro, {Patricio A.} and Alejandra Ramirez and Sep{\'u}lveda, {Fernando J.} and Christian Peters and Humberto Fierro and Javier Waldron and Sandra Luza and Jorge Fuentealba and Mu{\~n}oz, {Francisco J.} and {De Ferrari}, {Giancarlo V.} and Bush, {Ashley I.} and Aguayo, {Luis G.} and Carlos Opazo",
year = "2014",
doi = "10.3389/fnagi.2014.00319",
language = "English",
volume = "6",
journal = "Frontiers in Aging Neuroscience",
issn = "1663-4365",
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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, 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, vol. 6, n.º OCT, 319. https://doi.org/10.3389/fnagi.2014.00319

Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine : Modulation of synaptic activity in hippocampal neurons. / Castro, Patricio A.; Ramirez, Alejandra; Sepúlveda, Fernando J.; Peters, Christian; Fierro, Humberto; Waldron, Javier; Luza, Sandra; Fuentealba, Jorge; Muñoz, Francisco J.; De Ferrari, Giancarlo V.; Bush, Ashley I.; Aguayo, Luis G.; Opazo, Carlos.

En: Frontiers in Aging Neuroscience, Vol. 6, N.º OCT, 319, 2014.

Resultado de la investigación: Article

TY - JOUR

T1 - Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine

T2 - Modulation of synaptic activity in hippocampal neurons

AU - Castro, Patricio A.

AU - Ramirez, Alejandra

AU - Sepúlveda, Fernando J.

AU - Peters, Christian

AU - Fierro, Humberto

AU - Waldron, Javier

AU - Luza, Sandra

AU - Fuentealba, Jorge

AU - Muñoz, Francisco J.

AU - De Ferrari, Giancarlo V.

AU - Bush, Ashley I.

AU - Aguayo, Luis G.

AU - Opazo, Carlos

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Copper

KW - Dynamin

KW - Epileptiform-like activity

KW - Hyperexcitability

KW - Neocuproine

KW - Synapsin

KW - Synaptic activity

KW - Zinc

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U2 - 10.3389/fnagi.2014.00319

DO - 10.3389/fnagi.2014.00319

M3 - Article

AN - SCOPUS:84909595659

VL - 6

JO - Frontiers in Aging Neuroscience

JF - Frontiers in Aging Neuroscience

SN - 1663-4365

IS - OCT

M1 - 319

ER -