COPPER ON THE BRAIN AT REST
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."
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