In recent years it has been established that copper plays an essential role in the health of the human brain. Improper copper oxidation has been linked to several neurological disorders including Alzheimer’s, Parkinson’s, Menkes’ and Wilson’s.
Copper has also been identified as a critical ingredient in the enzymes that activate the brain’s neurotransmitters in response to stimuli. Now a new study by researchers with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) has shown that proper copper levels are also essential to the health of the brain at rest.
“Using new molecular imaging techniques, we’ve identified copper as a dynamic modulator of spontaneous activity of developing neural circuits, which is the baseline activity of neurons without active stimuli, kind of like when you sleep or daydream, that allows circuits to rest and adapt,” says Chris Chang, a faculty chemist with Berkeley Lab’s Chemical Sciences Division who led this study. “Traditionally, copper has been regarded as a static metabolic cofactor that must be buried within enzymes to protect against the generation of reactive oxygen species and subsequent free radical damage. We’ve shown that dynamic and loosely bound pools of copper can also modulate neural activity and are essential for the normal development of synapses and circuits.”
Chang , who also holds appointments with the University of California (UC) Berkeley’s Chemistry Department and the Howard Hughes Medical Institute (HHMI), is the corresponding author of a paper that describes this study in the Proceedings of the National Academy of Sciences (PNAS). The paper is titled “Copper is an endogenous modulator of neural circuit spontaneous activity.” Co-authors are Sheel Dodani, Alana Firl, Jefferson Chan, Christine Nam, Allegra Aron, Carl Onak, Karla Ramos-Torres, Jaeho Paek, Corey Webster and Marla Feller.
Although the human brain accounts for only two-percent of total body mass, it consumes 20-percent of the oxygen taken in through respiration. This high demand for oxygen and oxidative metabolism has resulted in the brain harboring the body’s highest levels of copper, as well as iron and zinc. Over the past few years, Chang and his research group at UC Berkeley have developed a series of fluorescent probes for molecular imaging of copper in the brain.
“A lack of methods for monitoring dynamic changes in copper in whole living organisms has made it difficult to determine the complex relationships between copper status and various stages of health and disease,” Chang said. “We’ve been designing fluorescent probes that can map the movement of copper in live cells, tissue or even model organisms, such as mice and zebra fish.”
For this latest study, Chang and his group developed a fluorescent probe called Copper Fluor-3 (CF3) that can be used for one- and two-photon imaging of copper ions. This new probe allowed them to explore the potential contributions to cell signaling of loosely bound forms of copper in hippocampal neurons and retinal tissue.
“CF3 is a more hydrophilic probe compared to others we have made, so it gives more even staining and is suitable for both cells and tissue,” Chang says. “It allows us to utilize both confocal and two-photon imaging methods when we use it along with a matching control dye (Ctrl-CF3) that lacks sensitivity to copper.”
With the combination of CF3 and Ctrl-CF3, Chang and his group showed that neurons and neural tissue maintain stores of loosely bound copper that can be attenuated by chelation to create what is called a “labile copper pool.” Targeted disruption of these labile copper pools by acute chelation or genetic knockdown of the copper ion channel known as CTR1 (for copper transporter 1) alters spontaneous neural activity in developing hippocampal and retinal circuits.
“We demonstrated that the addition of the copper chelator bathocuproine disulfonate (BCS) modulates copper signaling which translates into modulation of neural activity,” Chang says. “Acute copper chelation as a result of additional BCS in dissociated hippocampal cultures and intact developing retinal tissue removed the copper which resulted in too much spontaneous activity.”
The results of this study suggest that the mismanagement of copper in the brain that has been linked to Wilson’s, Alzheimer’s and other neurological disorders can also contribute to misregulation of signaling in cell−to-cell communications.
“Our results hold therapeutic implications in that whether a patient needs copper supplements or copper chelators depends on how much copper is present and where in the brain it is located,” Chang says. “These findings also highlight the continuing need to develop molecular imaging probes as pilot screening tools to help uncover unique and unexplored metal biology in living systems.”
This research was supported by the National Institutes of Health and the Howard Hughes Medical Institute.
Lawrence Berkeley National Laboratory addresses the world’s most urgent scientific challenges by advancing sustainable energy, protecting human health, creating new materials, and revealing the origin and fate of the universe. Founded in 1931, Berkeley Lab’s scientific expertise has been recognized with 13 Nobel prizes. The University of California manages Berkeley Lab for the U.S. Department of Energy’s Office of Science. For more, visit www.lbl.gov
Lynn Yarris | newswise
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy