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In Parkinson's Disease, the Brain Stops Playing by the 'Rules'


For release: Tuesday, February 24, 2009

Parkinson's disease (PD) slowly robs people of their ability to control movement.  Purposeful movements become slow and rigid, while periods of rest become interrupted by shakes and tremors.  In a study reported in Science*, researchers say they are closer to understanding how these symptoms arise, and possibly how to treat them.

PD attacks a brain structure called the substantia nigra, destroying neurons there that produce the chemical dopamine.  Treatment with levodopa, a precursor of dopamine, can provide some symptomatic relief in the early stages of the disease, but tends to lose potency over time.  With an eye toward better treatments, researchers have been asking how the loss of dopamine affects other parts of the brain, especially a brain structure called the striatum, the main target of the dopamine neurons lost in PD.

In the study, D. James Surmeier, Ph.D., a professor of physiology at Northwestern University in Chicago, examined what happens to connections (synapses) between the striatum and the cerebral cortex – the brain's outermost layer (cerebral cortex), which is involved in planning and executing movements.  He found that in mice, dopamine alters the plasticity of these cortical synapses – their ability to become stronger or weaker with experience.

Striatal neurons are considered important in PD because they receive input directly from dopamine-producing neurons in the substantia nigra; they are also believed to be key players in the brain circuitry that controls movement.  In prior studies of the striatum, however, researchers hit a stumbling block: There are two major types of striatal neuron, each with a different type of dopamine receptor, called D1 and D2.  Researchers suspected that the two types of neuron must behave very differently, but in viable brain tissue from mice, the neurons looked identical.

This led to confusion about how dopamine affects the striatum, says Dr. Surmeier, who is supported by the National Institute of Neurological Disorders and Stroke (NINDS). He overcame this obstacle by working with mice in which neurons expressing either D1 or D2 receptors were labeled with fluorescent proteins.  The mice were provided by the Gene Expression Nervous System Atlas (GENSAT) project, supported by NINDS and the NIH Neuroscience Blueprint.

"It was widely believed that plasticity at cortical synapses in the striatum is lost in PD," he says.  "Our findings show that plasticity is still there, but the rules have been distorted."

One of those rules is that if two neurons connected by a synapse are simultaneously active, the synapse can grow stronger or weaker depending on which neuron became active first.  Dr. Surmeier found that in mouse models of PD, the timing of activity no longer controls the direction of plasticity.  But the identity of the striatal neurons does.  With repeated pairing of cortical and striatal activity, the synapses on the striatal neurons with D1 receptors got weaker, whereas those with D2 receptors got stronger, regardless of timing.

Those changes might help explain the symptoms of PD, according to Dr. Surmeier. "We think that the neurons with D1 receptors are part of a 'go' circuit that enables the brain to select movements, whereas the neurons with D2 receptors are part of a 'no-go' circuit that suppresses movements," he says.

"In Parkinson's disease, it appears that the ability of experience to correctly shape the activation of these two circuits is lost. Without dopamine, the cortex appears to have a great deal of difficulty activating the 'go' circuit, whereas it becomes much too easy to activate the ‘no-go’ circuit," he says.  "This is consistent with the difficulty PD patients have in action selection. It’s as if no matter what the cortex tells the striatum, it tells the rest of the brain to stop."

Dr. Surmeier's study also provides a foundation for using pharmacological blockade of the chemical adenosine to treat Parkinson's disease, a strategy currently being tested in clinical trials.  He found that the abnormal strengthening of the "no-go," D2 synapse circuit that occurs in mouse models of PD was diminished by blocking adenosine receptors.

-By Daniel Stimson, Ph.D.

*Shen W, Flajolet M, Greengard P and Surmeier DJ.  "Dichotomous Control of Striatal Synaptic Plasticity."  Science, August 28, 2008, Vol. 321(5890), pp. 848-851.

Last Modified February 24, 2009