University of Western Ontario researchers have unlocked a secret inside the brain which could potentially improve the long-term outlook of those impacted by Parkinson’s disease.
A team of researchers at the Schulich School of Medicine & Dentistry’s Robarts Research Institute – which includes researchers Marco and Vania Prado – have demonstrated that the elimination of one of the neurotransmitters in the part of the brain associated with Parkinson’s disease may improve brain function without major adverse effects. The research has been published in the November edition of the prestigious journal PLoS Biology.
The Prado team used genetically modified mice, developed at Western, and high-level behavior/imaging techniques to study the function of neurons and neurotransmitters in the striatum, the region of the brain affected in Parkinson’s, Huntington’s and other motor diseases. The research team was particularly interested in the neurotransmitter acetylcholine, and what effect it has on brain function.
“The brain has different regions and we know the different brain regions can participate in different tasks or be affected in different diseases,” says Marco Prado, who has joint appointments in the Department of Physiology & Pharmacology and Anatomy & Cell Biology at Schulich.
In the striatum area of the brain there are several neurotransmitters, which are chemical messengers secreted by one neuron and used to communicate with another neuron. In Parkinsons’ disease, the levels of the neurotransmitter dopamine drop. At the same time, the neurons secreting another neurotransmitter, acetylcholine, become more active.
“We know a lot about what dopamine does in the brain, but for this particular neurotransmitter, acetylcholine, we don’t know much,” Marco Prado says. “In this brain region, we don’t know exactly what it does.”
The objective of the research was to try to understand what acetylcholine does to regulate the striatum. They wanted to see if blocking neurons secreting acetylcholine would be detrimental or cause any problems.
“If it doesn’t cause any problem, we can think in the future that we could use strategies to block those cells, for example in Parkinson’s disease, to try to see whether we could get improvement in the motor symptoms,” he says.
In the past, researchers approached this question by killing these neurons. However this resulted in adverse affects.
“The surprise was that we didn’t find the same things they found and the reason for that is, in fact, a number of people discovered the neurons secrete more than one neurotransmitter. If you kill the neuron, you are killing everything. What we did was genetically switch off just the release of one of the neurotransmitters,” Marco Prado says. “We were very surprised we could switch off the secretion of acetylcholine and we did not see as many effects as you would expect by looking at what people did in the past because they killed neurons.”
By using state-of-the-art genetic techniques to eliminate the secretion of acetylcholine in mice, the researchers were able to show the neurons that secrete acetylcholine are also responsible for a secondary function. These neurons secrete two different neurotransmitters that can regulate different behaviours depending on the neurotransmitters they secrete.
The neurons that secrete acetylcholine also secrete a neurotransmitter called glutamate. Prado and his colleagues found they could get rid of acetylcholine secretion without disturbing brain function.
“A lot of the effects people saw before were not only because of acetylcholine, but also because of glutamate. So now we have a way of selectively disrupting only the acetylcholine component. One of the main findings is … a given type of neuron can secrete two different types of chemical messengers and can regulate a circuitry and behaviour differently with the two different neurotransmitters,” he explains. “You add another layer of regulation and a novel target.”
The researchers also showed acetylcholine, glutamate and dopamine have a special relationship; they found the elimination of acetylcholine secretion boosted the actions of dopamine. This may have important applications to Parkinson’s disease because increased function of dopamine has been previously shown to improve motor symptoms in the disease.
Marco Prado says the next steps will be to eliminate acetylcholine secretion in Parkinson’s disease mouse models to see if there are improvements in the motor symptoms.
“By impairing the actions of acetylcholine, we increase those receptors specifically for dopamine,” he says. “When we injected those mice with drugs that mimic what dopamine does, they responded much, much more to those drugs than the normal mice.”
This research provides a better understanding of how this particular area of the brain works.
The hope is to produce a drug to block acetylcholine release selectively in the striatum. If their suspicions are correct, this should help in Parkinson’s disease by blocking the activity of these neurons without having any other negative effects on brain function.
The research was funded by the Canadian Institutes of Health Research, the Canada Foundation for Innovation and the Ontario Research Fund. The research team also included Monica Guzman, Xavier De Jaeger, Sanda Raulic, Ivana Souza, Alex Li, Susanne Schmid, Ravi Menon and Robert Bartha from Western; Marc Caron from Duke University Medical Center; and Raul Gainetdinov from the Italian Institute of Technology.
