Brain “Talk” Helps Researchers Discover Circuit Underlying Dyskinesia in Parkinson’s

In the September 2 edition of Neuron, researchers report the discovery of changes in the brain that happen in Parkinson's disease (PD) further downstream of where dopamine sends its message. They noted supersensitivity in these neurons that could also explain dyskinesia – the involuntary movements that often come with dopamine therapies. The study, which was supported in part by the Parkinson's Disease Foundation, points to potential targets for new PD medications.

When PD develops, there are many changes in the brain. For example, we know that the dopamine neurons lost in PD, along with other brain cells that control the body's movement "talk" to each other using chemical transmitters as their "language." In this conversation, intermediary cells called medium spiny neurons (MSNs) listen in to dopamine and translate it using: GABA (gamma aminobutyric acid).

Much PD research has focused on brain changes in the dopamine part of the conversation, pointing to those changes as responsible for the symptoms of PD. The same thinking led to research initially pointing to dopamine drugs (e.g., Sinemet) as the main culprit behind dyskinesias. Since then, research has suggested there is more at play to dyskinesia, such as changes further downstream of where the dopamine message is delivered in the brain, but disproving the original theory has been difficult.

Researchers including Anders Borgkvist, Ph.D., under the direction of David Sulzer, Ph.D., at the PDF Research Center at Columbia University Medical Center, wanted to better understand the entire brain circuitry, including the under-explored GABA part of the conversation and the role of MSNs that are the target of the dopamine message in the conversation. They studied the brains of mice with Parkinsonian symptoms, and used a variety of techniques to monitor communication in the brain.

Results

  • Normally, MSN cells listen for a dopamine message and then "speak" that message to other neurons using GABA as their language. They are able to regulate their own volume by not "speaking" too loudly (not releasing too much GABA if they don't have to).
  • In PD, when dopamine levels drop in the brain, two things happen: first, the dopamine-side of the conversation falls silent and second, as a result, MSN neurons, now deprived of stimulation by the dopamine message, become less active and release less GABA.
  • MSNs, because they are missing their usual message from dopamine, then become super sensitive to the dopamine message, tuning up their readiness to react to small traces of dopamine.
  • Because of this sensitivity, in PD mice treated with dopamine-replacing drugs like Sinemet®, the MSNs are activated again, but they now "speak" too loudly, releasing too much GABA.
  • This resulting release of too much GABA can lead to behaviors like dyskinesias.
  • In PD, to help MSNs "speak" normally again (and potentially ease dyskinesia) the researchers identified two chemical receptors that might be targets for potential PD therapies – not based on dopamine – GABAB receptors and cannabinoid receptor 1.

What Does It Mean?

To date, research has implicated the dopamine part of brain circuitry in PD symptoms. For a time, blame was placed on dopamine replacement drugs (Sinemet) as the sole cause of dyskinesia. Even though several studies showed that dyskinesia might result from changes in brain circuitry, it remained a mystery why or how this happened.

This paper improves our understanding of brain circuitry in PD by implicating a downstream pathway (one that usually receives dopamine conversation and to date, largely ignored) in the disease, and in dyskinesia. Specifically, researchers have found that in PD, abnormal changes in the brain circuit involving GABA cause long lasting "sensitivity" in the brain.

This should ease concerns of many people with PD about taking the drug Sinemet in their disease. Clinicians have been also recognizing that there is little basis for "saving" Sinemet for use later in the course of PD, since people with more advanced PD are still likely to develop dyskinesia quickly once exposed to Sinemet.

Overall the results point us toward a better understanding of dyskinesia and possible alternative therapies to treat it. After all, dyskinesias are a very common symptom for people with Parkinson's, but there are currently only two ways of treating them and neither is ideal. The first is to reduce a person's dosage of Sinemet (which in turn, worsens his or her symptoms) and the second option is to undergo deep brain stimulation surgery (not the right option for everyone).

What is most exciting about this PDF-supported basic science discovery is that the improved insight into brain circuitry has opened the door to alternative treatments — potential ways of controlling dyskinesias without altering the amount of Sinemet people take.

While further research is needed (this early research was conducted in animals), the discovery offers hope of controlling, if not preventing, dyskinesias without affecting a person's ability to move properly.

Reference

Borgkvist A, Avegno EM, Wong MY, Kheirbek MA, Sonders MS, Hen R and Sulzer D. Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice (2015) Neuronhttp://dx.doi.org/10.1016/j.neuron.2015.08.022

 

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