Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Keeping it local: Protecting the brain starts at the synapse

23.10.2013
New research by scientists at UC San Francisco shows that one of the brain's fundamental self-protection mechanisms depends on coordinated, finely calibrated teamwork among neurons and non-neural cells knows as glial cells, which until fairly recently were thought to be mere support cells for neurons.

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!
Further information:
http://www.ucsf.edu

More articles from Life Sciences:

nachricht Making fuel out of thick air
08.12.2017 | DOE/Argonne National Laboratory

nachricht ‘Spying’ on the hidden geometry of complex networks through machine intelligence
08.12.2017 | Technische Universität Dresden

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

Im Focus: Virtual Reality for Bacteria

An interdisciplinary group of researchers interfaced individual bacteria with a computer to build a hybrid bio-digital circuit - Study published in Nature Communications

Scientists at the Institute of Science and Technology Austria (IST Austria) have managed to control the behavior of individual bacteria by connecting them to a...

Im Focus: A space-time sensor for light-matter interactions

Physicists in the Laboratory for Attosecond Physics (run jointly by LMU Munich and the Max Planck Institute for Quantum Optics) have developed an attosecond electron microscope that allows them to visualize the dispersion of light in time and space, and observe the motions of electrons in atoms.

The most basic of all physical interactions in nature is that between light and matter. This interaction takes place in attosecond times (i.e. billionths of a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Midwife and signpost for photons

11.12.2017 | Physics and Astronomy

How do megacities impact coastal seas? Searching for evidence in Chinese marginal seas

11.12.2017 | Earth Sciences

PhoxTroT: Optical Interconnect Technologies Revolutionized Data Centers and HPC Systems

11.12.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>