Copper enhances cellular and network excitabilities, and improves temporal processing in the rat hippocampus

Abstract

Copper, an ion with many important metabolic functions, has also been proposed to have a role as modulator on neuronal function, mostly based on its effects on voltage- and neurotransmitter-gated conductance as well as on neurological symptoms of patients with altered copper homeostasis. Nevertheless, the mechanisms by which copper exerts its neuromodulatory effects have not been clearly established in a functional neuronal network. Using rat hippocampus slices as a neuronal network model, the effects of copper in the range of 10-100 nm were tested on the intrinsic, synaptic and network properties of the CA1 region. Most of the previously described effects of this cation were in the micromolar range of copper concentrations. The current results indicate that copper is a multifaceted neuromodulator, having effects that may be grouped into two categories: (i) activity enhancement, by modulating synaptic communication and action potential (AP) conductances; and (ii) temporal processing and correlation extraction, by improving reliability and depressing inhibition. Specifically it was found that copper hyperpolarizes AP firing threshold, enhances neuronal and network excitability, modifies CA3-CA1 pathway gain, enhances the frequency of spontaneous synaptic events, decreases inhibitory network activity, and improves AP timing reliability. Moreover, copper chelation by bathocuproine decreases spontaneous network spiking activity. These results allow the proposal that copper affects the network activity from cellular to circuit levels on a moment-by-moment basis, and should be considered a crucial functional component of hippocampal neuronal circuitry.

Copper signalling: causes and consequences

“…Copper can diffuse out of the synapse driven by the lower extrasynaptic concentration (1 μM ) [ 216 ]. Moreover, the extrasynaptic copper concentration has been estimated to be in the nanomolar range based on the cellular and network excitability produced by bath-applied copper in the CA1 area of the rat hippocampal slice [ 244 ]. (This effect was primarily explained by the ability of copper to interfere with Hodgkin–Huxley conductances rather than the synaptic effects of copper [ 255 ].)…”

“…Astroglia, a previously neglected cell type of the brain [ 340 ], operate a variety of copper-dependent metabolic functions [ 6 , 80 , 240 , 341 , 342 ]. For this reason, in addition to synaptic and extrasynaptic copper signalling by way of excitatory/inhibitory receptors and ionic channels [ 22 , 234 , 235 , 237 – 244 , 246 , 255 , 336 , 345 – 355 ], we place copper-dependent production of pAs in astrocytes [ 338 ] and correlated gap-junction modulation in the centre of this option. The proposed scheme conjectures activity-dependent changes of copper pools [ 179 , 180 ] and polyamines (pAs), produced by CuAOs in astrocytes.…”

“…Acting on its extrasynaptic receptor, GABA elevates tonic inhibition and enhances the fast (gamma band) neural oscillations [ 360 ]. These ways, the steady-state pA level in astrocytes determined by copper-dependent forming and consuming can be associated with neural circuit activity [ 244 , 255 , 362 ] …”

CuII(atsm) Attenuates Neuroinflammation

“…Copper is required for many critical neuronal processes and functions, including differentiation, cell signaling, and synaptic transmission ( D’Ambrosi and Rossi, 2015 ; Maureira et al, 2015 ; Hatori et al, 2016 ). Alterations to biometal homeostasis are implicated in several neurodegenerative diseases.…”

Biological Organization Principles: Biogenesis, Cognition and Evolution of Living Systems

“…In the APs, Biological Closure entails a dynamical aspect in which a systemic variable (i.e. a variable important to the organization like cell membrane potential (V m )) is under functional control [29]. In the case of V m , its moment by moment value is controlled by metabolic processes that themselves are a function of V m .…”