Featured Research

from universities, journals, and other organizations

Key Mechanism In Brain Development Pinpointed, Raising Question About Use Of Antiseizure Drug

Date:
October 12, 2009
Source:
Stanford University Medical Center
Summary:
Researchers have identified a key molecular player in guiding the formation of synapses -- the all-important connections between nerve cells -- in the brain. This discovery, based on experiments in cell culture and in mice, could advance scientists' understanding of how young children's brains develop as well as point to new approaches toward countering brain disorders in adults.

Researchers at the Stanford University School of Medicine have identified a key molecular player in guiding the formation of synapses — the all-important connections between nerve cells — in the brain. This discovery, based on experiments in cell culture and in mice, could advance scientists' understanding of how young children's brains develop as well as point to new approaches toward countering brain disorders in adults.

Related Articles


The new work also pinpoints, for the first time, the biochemical mechanism by which the widely prescribed drug gabapentin (also marketed under the trade name Neurontin) works. "We have solved the longstanding mystery of how this blockbuster drug acts," said Ben Barres, MD, PhD, professor and chair of neurobiology. The study shows that gabapentin halts the formation of new synapses, possibly explaining its therapeutic value in mitigating epileptic seizures and chronic pain. This insight, however, may lead physicians to reconsider the circumstances in which the drug should be prescribed to pregnant women.

The paper, to be published online Oct. 8 in the journal Cell, looks at the interaction between neurons — the extensively researched nerve cells that account for 10 percent of the cells in the brain — and the less-studied but much more common brain cells called astrocytes. Much work has been done on how neurons transmit electrical signals to each other through synapses — the nanoscale electrochemical contact points between neurons. It is the brain's circuitry of some 100 trillion of these synapses that allow us to think, feel, remember and move.

It is commonly agreed that the precise placement and strength of each person's trillions of synaptic connections closely maps with that person's cognitive, emotional and behavioral makeup. But exactly why a particular synapse is formed in a certain place at a certain time has largely remained a mystery. In 2005, Barres took a big step toward explaining this process when he and his colleagues discovered that a protein astrocytes secrete, called thrombospondin, is essential to the formation of this complex brain circuitry.

Still, no one knew the precise mechanism by which thrombospondin induced synapse formation.

In this new study, Barres, lead author Cagla Eroglu, PhD, and their colleagues demonstrate how thrombospondin binds to a receptor found on neurons' outer membranes. The role of this receptor, known as alpha2delta-1, had been obscure until now. But in an experiment with mice, the scientists found that neurons lacking alpha2delta-1 were unable to form synapses in response to thrombospondin stimulation.

And when the researchers grew neurons in a dish that were bioengineered to overexpress this receptor, those neurons produced twice as many synapses in response to stimulation with thrombospondin than did their ummodified counterparts.

The new discovery about alpha2delta-1's key role in synapse formation carries important implications for understanding the cause of pain and of epilepsy and developing improved medications for these conditions.

It was already known that alpha2delta-1 is the neuronal receptor for gabapentin, one of the world's most widely administered medications. Gabapentin is often prescribed for epilepsy and chronic pain, and its off-label use for other indications is widespread. Up to now, the molecular mechanism of gabapentin's action — what, exactly, it's doing to counter seizures or chronic pain — was unknown. But both syndromes may involve excessive numbers of synaptic connections in local areas of the brain.

In their new study, Barres and his colleagues found that when gabapentin was administered in developing mice, it bound to alpha2delta-1, preventing thrombospondin from binding to the receptor and, in turn, impeding synapse formation. Likewise, by blocking thrombosponin, gabapentin may reduce excess synapse formation in vulnerable areas of the human brain.

Barres noted that he and his colleagues found that gabapentin does not dissolve pre-existing synapses, but only prevents formation of new ones. That greatly diminishes gabapentin's potential danger to adults. In mature human brains, astrocytes ordinarily produce very little thrombospondin, and adult neurons don't form many new synapses, although some new synapses do continue to be formed throughout life — for example, in a part of the brain where new memories are laid down and at sites of injury to neurons, such as occurs after a stroke.

But the new findings raise questions about gabapentin's effect in situations where synapse formation is widespread and crucial, most notably in pregnancies. The vast bulk of the brain's synapses are formed during gestation and the very early months and years after birth. Because gabapentin easily crosses the placental barrier, it could potentially interfere with a fetus' rapidly developing brain just when global synapse formation is proceeding at breakneck speed.

"It's a bit scary that a drug that can so powerfully block synapse formation is being used in pregnant women," Barres said. "This potential effect on fetal brains needs to be taken seriously. Right now, doctors have the view that gabapentin is the safest anticonvulsant. There is no question that pregnant women with epilepsy who have been advised by their neurologists to continue their anticonvulsant treatment with gabapentin during their pregnancy should definitely remain on this drug until instructed otherwise. But there is no long-term registry being kept to track gabapentin-exposed babies. Our findings are saying that we need to be following up on these newborns so that their cognitive performance can be studied as they grow older."

Eroglu, then a postdoctoral researcher in Barres' laboratory, is now an assistant professor of cell biology at Duke University in Durham, N.C. Other Stanford co-authors were Nicola Allen, PhD; Michael Susman; Nancy O'Rourke, PhD; Chan Young Park, PhD; Engin Ozkan, PhD; Chandrani Chakraborty; Sara Mulinyawe; Andrew Huberman; PhD; Eric Green, MD, PhD; Ricardo Dolmetsch, PhD; Christopher Garcia, PhD; and Stephen Smith, PhD. Funding was provided by the National Institute of Drug Addiction; the National Heart, Lung and Blood Institute; the National Institutes of Health; the Human Frontiers Scientific Program and a Helen Hay Whitney postdoctoral fellowship.


Story Source:

The above story is based on materials provided by Stanford University Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Stanford University Medical Center. "Key Mechanism In Brain Development Pinpointed, Raising Question About Use Of Antiseizure Drug." ScienceDaily. ScienceDaily, 12 October 2009. <www.sciencedaily.com/releases/2009/10/091008123226.htm>.
Stanford University Medical Center. (2009, October 12). Key Mechanism In Brain Development Pinpointed, Raising Question About Use Of Antiseizure Drug. ScienceDaily. Retrieved November 26, 2014 from www.sciencedaily.com/releases/2009/10/091008123226.htm
Stanford University Medical Center. "Key Mechanism In Brain Development Pinpointed, Raising Question About Use Of Antiseizure Drug." ScienceDaily. www.sciencedaily.com/releases/2009/10/091008123226.htm (accessed November 26, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Wednesday, November 26, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Pet Dogs to Be Used in Anti-Ageing Trial

Pet Dogs to Be Used in Anti-Ageing Trial

Reuters - Innovations Video Online (Nov. 26, 2014) Researchers in the United States are preparing to discover whether a drug commonly used in human organ transplants can extend the lifespan and health quality of pet dogs. Video provided by Reuters
Powered by NewsLook.com
Today's Prostheses Are More Capable Than Ever

Today's Prostheses Are More Capable Than Ever

Newsy (Nov. 26, 2014) Advances in prosthetics are making replacement body parts stronger and more lifelike than they’ve ever been. Video provided by Newsy
Powered by NewsLook.com
From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

Newsy (Nov. 25, 2014) The US FDA is announcing new calorie rules on Tuesday that will require everywhere from theaters to vending machines to include calorie counts. Video provided by Newsy
Powered by NewsLook.com
Daily Serving Of Yogurt Could Reduce Risk Of Type 2 Diabetes

Daily Serving Of Yogurt Could Reduce Risk Of Type 2 Diabetes

Newsy (Nov. 25, 2014) Need another reason to eat yogurt every day? Researchers now say it could reduce a person's risk of developing type 2 diabetes. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins