title: Biphasic effects of copper on neurotransmission in rat hippocampal neurons.
abstract: The importance of copper in the CNS is well documented, but the mechanisms related to its brain functions are poorly understood. Copper is released at the synaptic cleft, where it may modulate neurotransmission. To understand the functional impact of copper on the neuronal network, we have analyzed the synaptic activity of primary rat hippocampal neurons by using different approaches including whole cell patch clamp, recording of calcium transients, immunofluorescence and western blot. Here, we show that copper produces biphasic changes in neurotransmission. When copper is acutely applied to the plate it blocks neurotransmission. Interestingly, when it is applied for 3 h to hippocampal neurons it mainly increases the frequency and amplitude of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)ergic currents (control: 0.21 ± 0.05 Hz/22.9 ± 1.3 pA; copper: 0.68 ± 0.16 Hz/30.5 ± 2.5 pA), intracellular calcium transients (control: 0.05 ± 0.013 Hz; copper: 0.11 ± 0.02 Hz) and evoked AMPA currents (control: EC50 8.3 ± 0.5 μM; copper: EC50 2.9 ± 0.2 μM). Moreover, our results suggest that copper increases GluA1 subunit levels of the AMPA receptor through the anchorage of AMPA receptors to the plasma membrane as a result of PSD-95 accumulation. We also found that copper-treated neurons displayed an undistinguishable neurotransmission to control neurons after 24 h of treatment, indicating that changes in neurotransmission induced by copper at 3 h of incubation are homeostatically regulated after long-term exposure to the metal. Together, our data reveal an unexpected biphasic effect of copper on neurotransmission, which may be relevant to understand the effects of this ion in brain diseases that display copper dyshomeostasis such as that observed in Alzheimer's disease (AD).
authors.affiliation: Laboratorio de Neurobiometales Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Chile.
authors.forename: Christian
authors.initials: C
authors.lastname: Peters
authors.forename: Braulio
authors.initials: B
authors.lastname: Muñoz
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Sepúlveda
authors.forename: Juan
authors.initials: J
authors.lastname: Urrutia
authors.forename: Mauricio
authors.initials: M
authors.lastname: Quiroz
authors.forename: Sandra
authors.initials: S
authors.lastname: Luza
authors.forename: Giancarlo V
authors.initials: GV
authors.lastname: De Ferrari
authors.forename: Luis G
authors.initials: LG
authors.lastname: Aguayo
authors.forename: Carlos
authors.initials: C
authors.lastname: Opazo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003300:Copper / Q000494:pharmacology*; D000076122:Disks Large Homolog 4 Protein; D055724:Electrophysiological Phenomena; D005260:Female; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects; D013569:Synapses / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018091:Receptors, AMPA; D003300:Copper