The study, which has implications for understanding neurodegenerative diseases, stroke, and other nervous system disorders, adds to a growing body of evidence that glial cells are integral to brain function.
Because this mechanism is localized at synapses, the sites where communication between neurons takes place, said Marta Margeta, MD, PhD, assistant professor of pathology and senior author of the new study, it ensures that protective measures will only be taken when and where they're most needed.
"The President needs more bodyguards than a Congressman, and with this system you can have your cake and eat it too: protection when you need it, without having to have it everywhere."
The brain is the body's hardest-working organ, consuming as much as 25 percent of our overall energy. This metabolic demand makes brain cells particularly vulnerable to damage from oxidative stress, in which reactive oxygen species (ROS), sometimes called free radicals, exert toxic effects on cellular components. ROS damage to neurons has been implicated in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions.
The brain can also be severely damaged when disease or injury—especially stroke—causes neurons to repetitively fire, flooding brain tissue with toxic levels of the excitatory neurotransmitter glutamate, a condition known as excitotoxicity.
To counteract the potential damage arising from ROS, excitotoxicity, and other dangers, animals including humans have evolved sophisticated physiological defenses such as the Nrf2 pathway, a molecular network that triggers the expression of a suite of protective genes when cellular function is under threat.
It is Neuroscience 101 that neurons pass on electrochemical messages at communication sites called synapses, but it is less well appreciated that the vast majority of synapses are "tripartite," consisting not just of a neuron sending a message and one receiving it, but also, nestled alongside each synapse, a star-shaped glial cell called an astrocyte.
Experiments in mouse models of Parkinson's disease and amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) have demonstrated that Nrf2-based neural protection is primarily conferred by astrocytes, but how neurons might alert astrocytes to stressful conditions is poorly understood.
In the new research, published October 21, 2013 in the Early Online Edition of Proceedings of the National Academy of Sciences, Margeta, former postdoctoral associate AgataHabas, PhD, now at UC San Diego, and colleagues teased apart the relative contributions of neurons and astrocytes in Nrf2 signaling by performing experiments on cell cultures containing predominantly neurons, predominantly astrocytes, or a mixture of both.
When the research team tried to activate the Nrf2 pathway in predominantly neural or astrocytic cultures by bathing them with a substance that creates conditions mimicking excitotoxicity, they had little success, but in mixed cultures the pathway was set in motion.
These experiments demonstrated that both neurons and astrocytes are necessary for Nrf2 activity. However, because the treatments affected the cultures globally and did not precisely target synapses, the researchers next applied substances that increase the firing of glutamate neurons by acting solely at synaptic sites. Again, Nrf2-related activity was observed only when astrocytes were present in cultures, but significantly, Nrf2 signaling increased in tandem with neuronal firing, suggesting that neurons calibrate Nrf2 activity in astrocytes to keep pace with neural activity.
This precise calibration remained intact even when there was no physical contact between neurons and astrocytes in culture, indicating that neurons secrete some soluble factor that activates Nrf2 in astrocytes.
When excitatory neurons fire and release glutamate neurotransmitter into the synapse, the released glutamate can reach nearby astrocytes, so glutamate seemed a good candidate for the neuronal messenger that induces Nrf2 activity. To test this idea, the scientists applied glutamate blockers to mixed cultures, which indeed prevented Nrf2 activation.
However, direct application of glutamate to astrocytes did not induce Nrf2 activity, which indicates that glutamate release is "necessary, but not sufficient" for Nrf2 regulation, and that future research may reveal other factors are at work at the synapse, Margeta said. In addition to the glutamate-secreting presynaptic neuron, the signal-receiving postsynaptic neuron and even the astrocyte itself may employ signaling molecules of their own to keep the system in balance, she said.
According to Margeta, the control system discovered by her lab keeps the brain from wasting energy on protection when it's unnecessary. "Too much of a good thing is not good, and I think that's why there's precise regulation," Margeta explained. "This system keeps baseline Nrf2 pretty low and in check, but if something bad happens, you can engage the system and ramp it up."
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospital.
Peter Farley | EurekAlert!
Flow of cerebrospinal fluid regulates neural stem cell division
22.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Chemists at FAU successfully demonstrate imine hydrogenation with inexpensive main group metal
22.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.
The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...
Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.
Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...
A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.
Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
18.05.2018 | Power and Electrical Engineering
18.05.2018 | Information Technology
18.05.2018 | Information Technology