Effects of copper on viability and functional properties of hippocampal neurons in vitro

Kapkaeva, Marina R.; Попова, О. В.; Kondratenko, R. V.; Rogozin, Pavel D.; Генрихс, Е. Е.; Stelmashook, E. V.; Skrebitsky, V. G.; Хаспеков, Л. Г.; Isaev, N. K.

doi:10.1016/j.etp.2017.01.011

Cited by 15 publications

(11 citation statements)

References 26 publications

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“…Despite having a relatively simple network organization, primary hippocampal neuron cultures also display similar network-wide synchronous bursting activity and are hence attractive experimental models for studying the interplay between individual neuronal activity, synaptic connectivity and network activity (41,42). To investigate whether MeCP2 deficiency affects functional maturation, primary hippocampal neurons were plated on top of MEA chips and were allowed to spontaneously form neural networks.…”

Section: (1-3) Igf-1 Reduces Network Hyperexcitability Of Mecp2-deficmentioning

confidence: 99%

Loss of MeCP2 in immature neurons leads to impaired network integration

Sun

Gao

Tidei

et al. 2018

Human Molecular Genetics

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Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations or deletions in Methyl-CpG-binding Protein 2 (MeCP2), a brain-enriched transcriptional regulator. MeCP2 is highly expressed during neuronal maturation and its deficiency results in impaired dendritic morphogenesis and reduced dendritic spine numbers in developing neurons. However, whether MeCP2 deficiency impacts the integration of new neurons has not been directly assessed. In this study, we developed a modified rabies virus-mediated monosynaptic retrograde tracing method to interrogate presynaptic integration of MeCP2-deficient new neurons born in the adult hippocampus, a region with lifelong neurogenesis and plasticity. We found that selective deletion of MeCP2 in adult-born new neurons impaired their long-range connectivity to the cortex, whereas their connectivity within the local hippocampal circuits or with subcortical regions was not significantly affected. We further showed that knockdown of MeCP2 in primary hippocampal neurons also resulted in reduced network integration. Interestingly, (1-3) insulin-like growth factor-1 (IGF-1), a small peptide under clinical trial testing for RTT, rescued neuronal integration deficits of MeCP2-deficient neurons in vitro but not in vivo. In addition, (1-3) IGF-1 treatment corrected aberrant excitability and network synchrony of MeCP2-deficient hippocampal neurons. Our results indicate that MeCP2 is essential for immature neurons to establish appropriate network connectivity.

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Section: (1-3) Igf-1 Reduces Network Hyperexcitability Of Mecp2-deficmentioning

confidence: 99%

Loss of MeCP2 in immature neurons leads to impaired network integration

Sun

Gao

Tidei

et al. 2018

Human Molecular Genetics

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“…It is important to reiterate that the effects of Cu, even across physiological (low micromolar) concentrations, appear to vary dramatically across brain regions and cell type (Doreulee et al., ; Shcheglovitov et al., ; Marchetti et al., ; Maureira et al., ; Hu, Ni, Duff‐Canning, & Wang, ; Kapkaeva et al., ). Moreover, while decreases in Cu levels can increase excitotoxicity as mentioned above, higher levels of exogenous Cu can also decrease cell viability through oxidative stress‐linked processes (Hua et al., ; Kapkaeva et al., ). Interestingly, SCN neurons are robustly resistant to glutamate excitotoxicity, and ERK1/2 signaling in SCN tissue has been reported to be neuroprotective against excess glutamate (Bottum, Poon, Haley, Karmarkar, & Tischkau, ; Karmarkar, Bottum, Krager, & Tischkau, ).…”

Section: Discussionmentioning

confidence: 99%

“…The effects on synaptic function result from Cu's role in both excitatory and inhibitory transmission, and may differ across brain regions depending on the distribution of neurotransmitter receptors. In hippocampal brain slices, one study observed that bath application of 10–100 nM Cu enhances neuronal activity (Maureira, Letelier, Alvarez, Delgado, & Vergara, ), while other studies found that NMDA currents, neuronal activity, and LTP are inhibited by 1 μM and 10 μM Cu (Doreulee, Yanovsky, & Haas, ; Kapkaeva et al., ) and that 20 μM Cu decreases cell viability through oxidative stress‐linked processes (Kapkaeva et al., ). Inhibition of hippocampal LTP was further demonstrated by dietary supplementation or chronic injection of Cu in vivo (Goldschmith, Infante, Leiva, Motles, & Palestini, ; Leiva, Palestini, Infante, Goldschmidt, & Motles, ).…”

Section: Introductionmentioning

confidence: 99%

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

Yamada

Prosser

2018

Eur J of Neuroscience

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The mammalian circadian clock in the suprachiasmatic nucleus (SCN) is very robust, able to coordinate our daily physiological and behavioral rhythms with exquisite accuracy. Simultaneously, the SCN clock is highly sensitive to environmental timing cues such as the solar cycle. This duality of resiliency and sensitivity may be sustained in part by a complex intertwining of three cellular oscillators: transcription/translation, metabolic/redox, and membrane excitability. We suggest here that one of the links connecting these oscillators may be forged from copper (Cu). Cellular Cu levels are highly regulated in the brain and peripherally, and Cu affects cellular metabolism, redox state, cell signaling, and transcription. We have shown that both Cu chelation and application induce nighttime phase shifts of the SCN clock in vitro and that these treatments affect glutamate, N‐methyl‐D‐aspartate receptor, and associated signaling processes differently. More recently we found that Cu induces mitogen‐activated protein kinase‐dependent phase shifts, while the mechanisms by which Cu removal induces phase shifts remain unclear. Lastly, we have found that two Cu transporters are expressed in the SCN, and that one of these transporters (ATP7A) exhibits a day/night rhythm. Our results suggest that Cu homeostasis is tightly regulated in the SCN, and that changes in Cu levels may serve as a time cue for the circadian clock. We discuss these findings in light of the existing literature and current models of multiple coupled circadian oscillators in the SCN.

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“…The experiments were carried out in accordance with the requirements of the "Rules for works with experimental animals" (Order No. Electrophysiological studies were performed on male Wistar rats aged 5-6 weeks according to the following procedure [25]. To determine the activity of hippocampal neurons, the animals were decapitated, and 3-4 transverse sections of the hippocampus were prepared and placed into a chamber with an incubation salt solution (ISS) heated to 28 • C. In this work, two ISSs were used: they were prepared in water with different deuterium contents.…”

Section: Methodsmentioning

confidence: 99%

Electrophysiological Activity and Survival Rate of Rats Nervous Tissue Cells Depends on D/H Isotopic Composition of Medium

et al. 2021

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The deuterium content modification in an organism has a neuroprotective effect during the hypoxia model, affecting anxiety, memory and stress resistance. The aim of this work was to elucidate the possible mechanisms of the medium D/H composition modification on nerve cells. We studied the effect of an incubation medium with a 50 ppm deuterium content compared to a medium with 150 ppm on: (1) the activity of Wistar rats’ hippocampus CA1 field neurons, (2) the level of cultured cerebellar neuron death during glucose deprivation and temperature stress, (3) mitochondrial membrane potential (MMP) and the generation of reactive oxygen species in cultures of cerebellar neurons. The results of the analysis showed that the incubation of hippocampal sections in a medium with a 50 ppm deuterium reduced the amplitude of the pop-spike. The restoration of neuron activity was observed when sections were returned to the incubation medium with a 150 ppm deuterium content. An environment with a 50 ppm deuterium did not significantly affect the level of reactive oxygen species in neuron cultures, while MMP decreased by 16–20%. In experiments with glucose deprivation and temperature stress, the medium with 50 ppm increased the death of neurons. Thus, a short exposure of nerve cells in the medium with 50 ppm deuterium acts as an additional stressful factor, which is possibly associated with the violation of the cell energy balance. The decrease in the mitochondrial membrane potential, which is known to be associated with ATP synthesis, indicates that this effect may be associated with the cell energy imbalance. The decrease in the activity of the CA1 field hippocampal neurons may reflect reversible adaptive changes in the operation of fast-reacting ion channels.

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Effects of copper on viability and functional properties of hippocampal neurons in vitro

Cited by 15 publications

References 26 publications

Loss of MeCP2 in immature neurons leads to impaired network integration

Loss of MeCP2 in immature neurons leads to impaired network integration

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

Electrophysiological Activity and Survival Rate of Rats Nervous Tissue Cells Depends on D/H Isotopic Composition of Medium

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