Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

CSHL scientists show in unprecedented detail how cortical nerve cells form synapses with neighbors

22.12.2010
How GABA transmission regulates synaptic adhesion at developing inhibitory synapses

Newly published research led by Professor Z. Josh Huang, Ph.D., of Cold Spring Harbor Laboratory (CSHL) sheds important new light on how neurons in the developing brain make connections with one another. This activity, called synapse validation, is at the heart of the process by which neural circuits self-assemble, and is directly implicated in pathology that gives rise to devastating neurodevelopmental disorders including autism and schizophrenia.

In the mammalian brain, even in its early stages of postnatal development, the cortex, the seat of cognition, is already an incredibly dense thicket of nerve cells. Throughout the cortex, in tiny spaces much too small too see, myriad neurons of various types are reaching out literally to touch others nearby—a prelude to the formation of synapses across which messages can propagate from cell to cell. A single nerve cell can "synapse" with many of its neighbors, at multiple points along the branching cables and filaments called axons and dendrites that emanate from the main nerve cell body. But not every neighbor will make a compatible partner, and validation is about finding the right ones.

It has been understood for some time that synapse formation is activity- or use- dependent. Although the mechanism has remained obscure, the emergence of a synpase has been known to involve some combination of preliminary transmission of messages between two neurons—a kind testing of the compatibility of a connection—and a process called cellular adhesion that brings the two cells into physical contact.

In their new study, published online ahead of print December 13th in Proceedings of the National Academy of Sciences, Huang and graduate student Yu Fu used a sophisticated imaging method called two-photon microscopy to observe synapse validation for the first time in living cortical circuits. They focused on a particular type of inhibitory neurons, called GABAergic because they communicate via neurotransmitters called GABA (gamma-aminobutyric acid).

"The question is: how can you form synapses with the right partners?" says Huang, "and what mechanism is involved to achieve the necessary specificity?" Some have proposed that nerve cells secrete some kind of repulsive or attractive molecules. "But when you are in the cortex, the distance between different potential partners is so minute—it's inconceivable that kind of mechanism could work."

"It's more plausible that the cortical neuron's strategy is to initiate synapse formation with almost any nearby target and then to test it, by trying to communicate using synaptic transmission," Huang explains. "Most of these tentative connections don't prove to be correct and will be eliminated. Only those between functionally compatible neurons will be validated and strengthened."

Building upon the knowledge that cellular "glues," in the form of cell-adhesion molecules called neurexins and neuroligins, are needed to make a preliminary connection, Huang and Fu observed in live cortical circuits precisely how they interacted. "They work like a zipper: two neurons—called pre-synaptic and post-synaptic—are touching; there are adhesion molecules coming from both sides, and they actually lock," Huang says.

Their key finding concerns the steps that occur following this preliminary zippering: the presynaptic neuron sends a quantity of neurotransmitter across to the prospective partner. But how does this neurotransmission get translated into molecular adhesion? Huang and Fu looked closely at neurexins, proteins that interact with neuroligins to form the zipper that holds synapses together. They found for the first time that two forms of neurexin, called alpha and beta, have very different properties, and respond in different ways to neural activity.

"The alpha neurexin molecule seems to be acting like a search engine," says Huang. Widely distributed along an axon, "it's searching everything." When it finds a potential partner, it then couples to the neurotransmitter machinery and the presynaptic cell begins to release neurotransmistter, to test the connection. "If the connection is good, then the beta neurexins come in and make a much tighter lock between the two nerve cells at the new synapse."

According to Huang, in comparatively simple model systems such as worms and flies, such connections are thought to be largely genetically hard-wired. "But in vertebrates, delicate structures like the hippocampus and the cerebral cortex probably require a finer system, which can respond to the organism's experiences. In other words, synaptic validation and strengthening is likely to be a learning-based system."

This suggests the connection between neurexins and other cell-adhesion molecules in the brain and neurodevelopmental disorders such as autism. A mutation in a gene called neurexin-1 and another encoding its receptor, neuroligin, have repeatedly been linked with autism in past studies. "These genes are known to be broadly expressed in many places of the nervous system," says Huang. "But the question is how and why changes in these genes leads to autism. There is some evidence that these changes do alter synapses. Our study suggests that such changes in synaptic adhesion molecules can impact a particular type of GABAergic synapse that has been shown to play an important role in regulating neural network operation."

Huang's CSHL laboratory will continue to explore the functional significance of neurexins and neuroligins in neurocircuits in living animals, and will attempt to relate changes in their expression with behavior.

"Differential dynamics and activity-dependent regulation of á- and â-neurexins at developing GABAergic synapses," appeared online ahead of print December 13, 2010 in Proceedings of the National Academy of Sciences. The authors are Yu Fu and Z. Josh Huang. the paper can be obtained online at doi: 10.1073/pnas.1011233108.

About Cold Spring Harbor Laboratory

Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL is ranked number one in the world by Thomson Reuters for impact of its research in molecular biology and genetics. The Laboratory has been home to eight Nobel Prize winners. Today, CSHL's multidisciplinary scientific community is more than 400 scientists strong, and its Meetings & Courses program hosts more than 8,000 scientists from around the world each year. The Laboratory's education arm also includes a graduate school and programs for undergraduates as well as middle and high school students and teachers. CSHL is a private, not-for-profit institution on the north shore of Long Island. For more information, visit www.cshl.edu.

Peter Tarr | EurekAlert!
Further information:
http://www.cshl.edu

More articles from Health and Medicine:

nachricht How cancer metastasis happens: Researchers reveal a key mechanism
19.01.2018 | Weill Cornell Medicine

nachricht Researchers identify new way to unmask melanoma cells to the immune system
17.01.2018 | Duke University Medical Center

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | 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

 
Latest News

Let the good tubes roll

19.01.2018 | Materials Sciences

How cancer metastasis happens: Researchers reveal a key mechanism

19.01.2018 | Health and Medicine

Meteoritic stardust unlocks timing of supernova dust formation

19.01.2018 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>