At The Synapse: Gene May Shed Light On Neurological Disorders

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At The Synapse: Gene May Shed Light On Neurological Disorders

http://www.medicalnewstoday.com/articles/108526.php

In our brains, where millions of signals move across a network of

neurons like runners in a relay race, all the critical baton passes

take place at synapses. These small gaps between nerve cell endings

have to be just the right size for messages to transmit properly.

Synapses that grow too large or too small are associated with motor

and cognitive impairment, learning and memory difficulties, and other

neurological disorders.

In a finding that sheds light on this system, researchers at the

University of Wisconsin-Madison describe a gene that controls the

proper development of synapses, which could help explain how the

process works and why it sometimes goes wrong.

Reporting in the journal Neuron, a team of geneticists in the College

of Agricultural and Life Sciences reveal the role of a gene in fruit

flies called " nervous wreck " that prevents synapses from overgrowing

by damping the effects of a pro-growth signal. Mutations in a human

version of " nervous wreck " have been linked to a severe genetic

developmental disability, and these findings may eventually help

scientists develop treatments for this and other neurological

disorders.

" The precise regulation of synaptic growth - not too much and not too

little - is a complex biological process, " says Kate O'Connor-Giles,

a postdoctoral fellow in the genetics department who led the

study. " We really need to have a deep understanding of how all the

factors involved are working together to develop rational treatments

for neurological disorders associated with aberrant synaptic growth. "

That's no small task. The brain is the most complex organ in the

body, containing a hundred billion nerve cells that branch out and

make trillions of connections to other neurons, muscle cells and

other cell types. Although an estimated 50 million Americans have

some kind of neurological disorder, in the majority of cases the

underlying cause is unknown. Improper synaptic growth may explain a

portion of these unknown cases.

To crack this complex system, O'Connor-Giles studies a particular

type of synapse in fruit flies, known as the neuromuscular junction,

which is relatively easy to examine and closely resembles the

synapses found in the central nervous system of humans. She works

with a particular kind of fly that is unable to produce functional

Nervous wreck protein, one of a collection of mutant flies engineered

more than 20 years ago by UW-Madison geneticist Barry Ganetzky, in

whose laboratory the study was completed with the help of researcher

Ling Ling Ho. This collection has been the source of many seminal

discoveries in brain science over the years.

Using genetic, biochemical and imaging techniques, O'Connor-Giles

showed that the " nervous wreck " protein appears to be part of an

important protein complex that helps regulate the density of certain

receptors on the surface of the nerve cell at the synapse. In

particular, the new findings suggest that the protein complex

decommissions receptors that respond to pro-growth signals coming

from the well-studied BMP signaling pathway. When the protein complex

is working properly, it moves the receptors back inside the nerve

cell - where they can no longer receive and respond to the pro-growth

signal - at the appropriate time.

" 'Nervous wreck' and (the other proteins in the complex) work

together to attenuate a positive growth signal, " says O'Connor-

Giles. " So when it's time for synaptic growth to stop, they are the

proteins that ensure the neuron stops listening to the positive

growth signal and stops growing.

When 'nervous wreck' is absent, you get synapses that are much too

large. " Problems with other proteins in the complex also lead to

synaptic overgrowth in fruit flies and, O'Connor-Giles predicts, may

contribute to developmental disabilities in humans as well.

Although her work was done in synapses undergoing initial formation,

these findings likely apply to adult brain cells, too. Inside fully

formed brains, neural connections grow and change over time in

response to experiences, a process called plasticity.

" The presumption is that the same mechanisms that are at play during

the initial formation of synapses are then recruited later in life

when these synapses need to be modified in response to experience or

injury, " says O'Connor-Giles. " So by understanding the initial

development of synapses, we may also be getting at the molecular

mechanisms underlying plasticity. "

These findings add to the big picture of how synaptic growth works, a

picture that in the long run will help scientists develop treatments

for various neurological disorders.

" Being able to manipulate synaptic growth is going to be crucial for

treating traumatic spinal chord injuries, " says O'Connor-Giles. " It's

also going to be important for treating a broad array of other

disorders, including epilepsy and developmental disabilities. "