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'Reset Switch' for Brain Cells Discovered

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Duke Health News 919-660-1306

DURHAM, N.C. -- Duke University Medical Center
neurobiologists have discovered how neurons in the brain
"reset" when they are overly active. This molecular reset
switch works to increase or decrease the sensitivity of brain
cells to stimulation by their neighbors. Such "homeostatic
plasticity" is critical for the brain to adapt to changes in
the environment -- either to avoid having its neurons swamped
by increased activity of a neural pathway, or rendered too
insensitive to detect triggering impulses from other neurons
when neural activity is low. This plasticity is distinct from
the more rapid changes in neural circuits laid down early
during the formation of memories, said the scientists.

According to the researchers, their basic studies provide
long-sought clues to how neurons protect themselves during
stroke, epilepsy, and spinal cord injury. Also, their findings
may help explain diverse brain changes that occur during early
childhood and that go awry in later stages of life in
Alzheimer's or Parkinson's disease.

The researchers, led by Assistant Professor of Neurobiology
Michael Ehlers, M.D., published their findings in the Oct. 30,
2003, issue of the journal Neuron. Other authors are
Yuanyue Mu, Ph.D., Takeshi Otsuka, Ph.D., April Horton and
Derek Scott. The research was supported by the National
Institutes of Health, the American Heart Association and a
Broad Scholars Award.

According to Ehlers, homeostatic plasticity has long been
theorized to exist and recently demonstrated in mammalian
neurons, but no mechanism for the process had been discovered.
Neuroscientists believed that such plasticity somehow adjusted
the global sensitivity of the myriad connections, called
synapses, that a neuron makes to its neighbors. At each of
these synaptic connections, one neuron triggers the firing of a
nerve impulse in another by launching a burst of chemicals
called neurotransmitters across a gap called the synaptic
cleft.

Such homeostatic plasticity takes place over periods of
hours or days and adjusts all a neuron's synapses, said Ehlers.
In contrast, the synaptic adjustments that underlie rapid
learning take place within seconds.

"Neurobiologists have understood that a neuron can increase
only so much its firing rate in response to inputs from other
neurons, and then it saturates," said Ehlers. "There had to be
a way for a neuron to recalibrate -- to scale up or down to
stay within an optimal dynamic firing frequency range.

"Consider when you're driving a car with a manual
transmission. As you accelerate, you reach a point where the
engine's RPMs are maximal and can go no higher. At that point,
you need to switch gears to bring back your RPMs to an optimal
range. What we have found is the molecular clutch that allows
neurons to shift gears" said Ehlers. "This really is a
profoundly important discovery. Imagine if your brain could
only operate in 'second gear,'" he said.

Although homeostatic plasticity had been a theory, only in
the last couple of years has its existence been confirmed
functionally, said Ehlers, and its mechanism was a mystery. It
was known that the process involved changing the number of
neurotransmitter receptors -- the proteins on the surfaces of
synapses that serve as receiving stations for
neurotransmitters. One key type of receptor implicated in such
changes is called the NMDA receptor -- a major component of
molecular learning and memory. The level of NMDA receptors was
known to increase or decrease over time periods consistent with
homeostatic plasticity, said Ehlers.

Using an array of analytical techniques, Ehlers and his
colleagues showed that the level of NMDA receptors was
controlled throughout a neuron by the processing of its initial
genetic blueprint -- called messenger RNA (mRNA). Messenger RNA
is a copy of the genetic DNA blueprint for a specific protein
-- such as the NMDA receptor protein -- that the cell's
protein-making machinery uses to manufacture the protein.

Specifically, the researchers' experiments revealed that
when a neuron needs to increase its overall sensitivity, the
stringlike mRNA blueprint for the NMDA receptor is snipped
apart and spliced back together slightly differently than when
the neuron needs to decrease its sensitivity.

This "alternate splicing" causes the production of an NMDA
protein differing in one small bit that attaches it to the
transport machinery that carries receptors to the synaptic
surface, found the Duke neurobiologists. When the overall
triggering of a neuron decreases, and the neuron needs greater
sensitivity -- and thus more NMDA receptors -- the alternate
mRNA splicing yields a receptor protein with a variant of this
bit that encourages the receptor to attach to the transport
machinery.

"It's a very surprising mechanism, and it explains a lot,"
said Ehlers. "It explains why the process is relatively slow,
because the process of changing splicing of new proteins would
be slow. And it explains how this process can happen at all the
synapses on a neuron, because it happens in the neuron's
nucleus, where mRNA splicing happens."

According to Ehlers, the findings by him and his colleagues
could aid understanding of how brain tissue is damaged during
stroke, and altered in pathological states of addiction or
following injury.

"For example, it's been known for some time that the
circuitry of the spinal cord is altered in response to spinal
cord injury, enhancing the NMDA receptor-mediated transmission
of nerve impulses," said Ehlers. "This aberrant rewiring causes
all kinds of problems in patients, including heart arrhythmias
and hypertension," he said. "So, our studies could lead to new
therapeutic approaches for treating such problems by targeting
the alternate splicing of mRNA for NMDA receptors."

More broadly, said Ehlers, "these findings could open a
floodgate of studies to determine where else in the brain
alternate splicing is used as a central control mechanism. It
is known that the brain uses alternate splicing more than any
other organ, but until now there has not been an experimental
system in which a specific alternate splicing event could be
controlled and studied.

"We have identified a completely new cellular signaling
pathway, and it's going to be quite exciting to unravel how it
works," said Ehlers. "Potentially this could open a whole new
window into a very fundamental aspect of neuronal
function."

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