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Duke University Medical Center

Synchronous neuronal firing may underlie Parkinson's disease
DURHAM, N.C. -- In a finding that contradicts current theories behind
Parkinson's disease, neuroscientists at Duke University Medical Center have
discovered in mice that critical nerve cells fire all at the same time and
thus overwhelm the brain's ability to control the body's movements.
Previously, scientists had thought that the abnormal body movements
characteristic of Parkinson's resulted from nerve cells in a specific brain
region called the motor cortex firing at a decreased rate, though still in
an ordered manner.
"Imagine an orchestra playing a beautiful symphony, with each instrument
playing a different part, but in harmony. That is the way the brain normally
works, with nerve cells sending different but coordinated signals throughout
the brain," said senior study investigator Miguel Nicolelis, M.D., Ph.D.,
Anne W. Deane Professor of Neuroscience. "We found that in an animal model
of Parkinson's, nerve cells seem to fire all at the same time, rather than
in harmony. It's like having all instruments playing the same note over and
over again at the same time during the symphony, rather than the different
instruments playing at different times."
Although the researchers made their discoveries in genetically engineered
mice, they believe the same processes may occur in humans.
The findings may help researchers to better understand Parkinson's disease
and to develop new therapeutics for the debilitating disorder, said lead
study investigator Rui Costa, D.V.M., Ph.D., chief of the section of in vivo
neural function at the National Institutes of Health, who launched this
study as a postdoctoral fellow in Nicolelis' laboratory.
"Therapeutic interventions that restore the normal synchrony of these
neurons in the brain may potentially be beneficial in treating Parkinson's
disease," Costa said.
The researchers published the findings in the Oct. 19, 2006, issue of the
journal Neuron. The work was funded by the National Institutes of Health,
the Hereditary Disease Foundation and the Anne W. Deane chair endowment to
Nicolelis.
Parkinson's disease is the second most common neurodegenerative disorder in
the United States, surpassed only by Alzheimer's disease. Approximately 1
million Americans have Parkinson's disease, and more than 50,000 new cases
are diagnosed each year. The symptoms of Parkinson's disease include tremors
or trembling, general slowness of movement, stiffness or rigidity of
muscles, and difficulty maintaining balance and gait.
Parkinson's disease results from the loss of nerve cells, or neurons, that
produce an important brain chemical called dopamine. Neurobiologists
previously believed that the tremors and muscular rigidity of this disease
were caused by decreases in the activity of neurons in the motor cortex.
Dopamine is a neurotransmitter, a chemical that neurons release to their
neighbors to signal them to fire nerve impulses. Dopamine is known to
control movement, balance, emotion, and the sense of pleasure.
Normally, when a signal needs to travel through the brain, neurons release
dopamine to transport the signal across the gap, or synapse, between
neurons. A kind of protein pump, called a transporter, recycles dopamine
back to the signaling neurons to prepare for the next burst of signal.
In studies 10 years ago, Marc Caron, Ph.D., James B. Duke professor of cell
biology at Duke and a co-investigator in the current study, used the
techniques of genetic engineering to produce a strain of mice that lacked
this protein transporter. Treatment of these mice with a chemical that
completely stops the production of dopamine resulted in mice that quickly
ran out of their supply of the neurotransmitter. The treated mice became
rigid and immobile, displaying symptoms similar to those experienced by
patients with Parkinson's disease.
In the current study, the researchers measured the electrical activity
simultaneously in the motor cortex and the striatum, another critical area
of the brain, in these dopamine-depleted mice. Communication of signals
among the neurons in these regions controls movement, balance and walking,
and it is this communication that is disabled in Parkinson's disease.
Using electrodes finer than a human hair implanted into individual neurons,
the researchers could monitor signals passed among neurons in the treated
mice. They found the overall level of activity of the neurons in the motor
cortex did not change. Instead, the neurons fired in unison, leaving the
Parkinsonian mice unable to direct or control their movement in a normal
manner.
In another part of the study, the researchers found evidence that may
provide insight into the underlying biology of schizophrenia. In these
tests, the researchers examined mice not treated with the dopamine-blocking
chemical, as the excess dopamine that accumulates in the brains of such
animals is known to make them exhibit the bizarre behaviors experienced by
people with schizophrenia.
It turned out that the excessive dopamine caused the mice's neurons to fire
in a less synchronous manner, just the opposite of what happened in the
Parkinsonian mice, the researchers said.
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Other researchers who participated in the study were Shih-Chieh Lin, Tatyana
Sotnikova, Michael Cyr and Raul Gainetdinov.

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