New Neuronal Signaling Pathway
Breaks All the Rules
by Dan Ferber
Researchers have discovered an entirely new way of passing messages
between brain cells. Rather than shuttling a chemical messenger between
two neurons, the brain uses an intermediary cell called an astrocyte,
which until now has been thought to play only a supporting role in neural
signaling. The chemical messenger itself is a highly unusual inverted amino
acid that occurs nowhere else in the body.
The new signaling system offers researchers a new target for drugs to
head off the massive brain damage that occurs following a stroke, says
Solomon Snyder of the Johns Hopkins School of Medicine, who
presented the results in a special lecture today to several thousand
neuroscientists.
The messenger, called D-serine, works in concert with a neurotransmitter
called glutamate to cause neurons to fire, Snyder says.
Brain circuits that use glutamate as a messenger are primary targets for
anti-stroke drugs, Snyder says. That's because there is a 50-fold increase
in glutamate release following a stroke, which overexcites nearby brain
cells and kills them, causing much more extensive brain damage than that
caused by the initial stroke. All the major drug companies have tried to
block glutamate signaling at the glutamate receptor called the NMDA
receptor, but existing anti-stroke drugs that worked well in animals have
failed in clinical trials, Snyder says.
Drugs that block the system may also help treat chronic
neurodegenerative diseases like Parkinson's, Huntingon's, and
Alzheimer's by preventing brain cells from becoming chronically
overexcited, which causes them to die off over a period of many years,
Snyder adds.
Snyder is careful to note that he owns stock in, and is on the advisory
board of Guilford Pharmaceutical, Inc. in Baltimore, Maryland. Johns
Hopkins University has licensed the patent on new technology being
developed by Snyder's team to Guilford.
Researchers already knew that glutamate signaling was unusual. Most
neurons use a single chemical message, or neurotransmitter, to pass
signals between them. But researchers discovered 11 years ago that
neurons that use glutamate also require another neurotransmitter. The
brain is thought to require two messengers to act hand in hand as a
fail-safe mechanism to prevent brain cells from becoming overexcited by
glutamate under ordinary circumstances.
For the past decade, most researchers thought that the second
neurotransmitter was another amino acid called glycine, because both
glycine and glutamate spurred the neurons to fire. But that theory didn't
sit well with Snyder. A large pool of glycine exists in the brain, so it was
not likely to work well as a safety to prevent neurons from going haywire.
Instead, the Hopkins team learned that D-serine, not glycine, was found
in the same parts of the brain, and the same brain cells, as the NMDA
receptor. What's more, an enzyme they discovered that breaks down
D-serine blocked glutamate-using neurons from firing, which strongly
implied D-serine was the messenger, Snyder says. Some of that work
was published in Proceedings of the National Academy of Sciences in
April.
In recent work that is not yet published, Snyder's lab showed that
transgenic mice that can't make D-serine are uncoordinated and stumble
when they walk, proving the new signaling system plays a key role in live
animals. The lack of coordination suggests that the new circuits reside in
the cerebellum.
The researchers are still breeding enough of the mice to do more
experiments, but they will eventually check for other brain abnormalities,
Snyder adds.
Other work has shown that the system works in an unusual way.
Glutamate passes from the signaling neuron to the receiving neuron in the
customary fashion. But the same glutamate released in the synapse also
drifts over to a nearby astrocyte, which cradles the synapse. Astrocytes,
which are a type of glial cell, have generally been thought only to be
supporting elements providing nutrition to neurons.
The astrocyte responds by activating enzymes that make D-serine and
pumping it out. D-serine then acts in concert with glutamate to spur the
NMDA receptor to fire.
The work is "a real tour de force," says Dennis Choi of Washington
University, president of the Society for Neuroscience. Both the use of an
inverted amino acid and the participation of astrocytes in brain cell
signaling is novel. "There's no precedent for this," he says.
Dan Ferber is a freelance science writer based in
Urbana, Illinois. |
