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 Progress in Super-Resolution Microscopy
17.12.2018 | Julius-Maximilians-Universität Würzburg

nachricht Communication between neural networks
17.12.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Data storage using individual molecules

Researchers from the University of Basel have reported a new method that allows the physical state of just a few atoms or molecules within a network to be controlled. It is based on the spontaneous self-organization of molecules into extensive networks with pores about one nanometer in size. In the journal ‘small’, the physicists reported on their investigations, which could be of particular importance for the development of new storage devices.

Around the world, researchers are attempting to shrink data storage devices to achieve as large a storage capacity in as small a space as possible. In almost...

Im Focus: Data use draining your battery? Tiny device to speed up memory while also saving power

The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.

Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

Im Focus: New Foldable Drone Flies through Narrow Holes in Rescue Missions

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

When a fish becomes fluid

17.12.2018 | Studies and Analyses

Progress in Super-Resolution Microscopy

17.12.2018 | Life Sciences

How electric heating could save CO2 emissions

17.12.2018 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>