Developing nervous system sculpted by opposing chemical messengers

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Developing nervous system sculpted by opposing chemical messengers

04 Jun 2005 Medical News Today

A newborn baby moves, breathes and cries in part because a network of

nerves called motor neurons carry signals from the infant's brain and

spinal cord to muscles throughout its body.

Thanks to new research by scientists at the Salk Institute for

Biological Studies, we are closer to understanding how these

complicated network connections are wired up during embryonic

development. Salk researchers have discovered that the same chemicals

(called neurotransmitters) that are responsible for nerve signals are

also involved in the wiring of synapses, the network's crucial

contact points between nerves, or between nerves and muscle cells.

The study, published in the May issue of the journal Neuron, showed

that as the motor neurons grow from their home base in the spinal

cord towards muscles throughout the body, they release two opposing

chemical signals. These signals act to preserve synapses that link a

motor neuron to its correct muscle cell. 'Spare' sites for potential

synapses that fail to team up with a motor neuron are dismantled.

" Our study provides the first evidence in a living animal system that

the neurotransmitters themselves are sculpturing the developing

nervous system, " said Kuo-Fen Lee, Associate Professor at the Salk,

who heads the research team reporting its results in Neuron.

Using mice as a model for human biology, Lee and colleagues showed

that each long, thin muscle cell in the developing embryo prepares

for the arrival of its motor neurons by creating sites for many

potential synapses along its length. However, three weeks after

conception, all the sites have disappeared, except those that

connected with a newly arrived motor neuron and formed a fully

functioning synapse. The scientists wanted to know: how does the

embryo 'weed out' the potential synapse sites that are not needed?

The answer to this question is crucial because it might shine light

on how the nervous system could make new connections in medical

conditions such as spinal cord injury.

Lee, along with Salk colleagues Weichun Lin, Bertha Dominguez, Jiefei

Yang, Prafulla Aryal, Eugene and Fred Gage, discovered that

the creation of synapses is controlled by the nerves themselves. As

they grow towards the muscle cells, the nerve cells release a

powerful chemical messenger from their growing ends. Called

acetylcholine, this neurotransmitter 'edits out' the potential

synapse sites on the muscle cell not destined to connect to a nerve.

In mature animals, acetylcholine is a key neurotransmitter

responsible for transmitting signals between nerve cells and muscle.

Using a combination of genetic and pharmacological techniques to

block the various components of the chemical pathways involved, the

Salk researchers painstakingly showed that acetylcholine works in

tandem with another chemical produced by nerve cells, called agrin.

Where the end of the nerve touches the muscle cell, agrin is

concentrated enough to overcome the 'editing' effect of the

acetylcholine. Further away from the nerve end, the levels of agrin

are not high enough to overcome the more powerful influence of

acetylcholine, and the redundant synapse sites are dismantled.

" The result is an interesting mechanism whereby two opposing forces

work together to create the crucial synaptic connections between

motor neurons and muscle cells, " said co-author Prafulla Aryal.

" Although we have suspected for 25 years that something like this was

happening, until now no-one has been able to demonstrate it in a

living system, " said Lee. " It is likely that this process occurs all

over the nervous system. If you're going to repair or regenerate

nerves in, for example, spinal cord injury you need to know how to

form synapses for the right connections to be made. "

The Salk Institute for Biological Studies in La Jolla, California, is

an independent nonprofit organization dedicated to fundamental

discoveries in the life sciences, the improvement of human health and

the training of future generations of researchers. Jonas Salk, M.D.,

whose polio vaccine all but eradicated the crippling disease

poliomyelitis in 1955, opened the Institute in 1965 with a gift of

land from the City of San Diego and the financial support of the

March of Dimes.

Salk Institute

http://www.salk.edu