Long-term use of L-DOPA (levodopa), the most effective treatment for Parkinson’s disease, commonly leads to a movement problem called dyskinesia, a side effect that can be as debilitating as Parkinson’s disease itself.The latest issue of Science Daily reports on the discovery by a team at Columbia University, New York, of the underlying mechanism.
Using a new method for manipulating neurons in a mouse model of Parkinson’s, a Columbia University Medical Center (CUMC) research team found that dyskinesia arises when striatonigral neurons become less responsive to GABA, an inhibitory neurotransmitter. This suggests that it may be possible to modulate the activity of these neurons to prevent or delay this disabling side effect. The paper was published recently in the online edition of Neuron.
Most studies into the cause of dyskinesia in Parkinson’s have focused on the dopamine receptors that remain in the brain, which over time become over-reactive to L-DOPA therapy. However, the CUMC team decided to look at how neurons of the basal ganglia regulates movement in the absence of dopamine.
The CUMC team employed a novel form of optogenetics, a technique that uses light to control neurons that have been genetically sensitized to light, and found that after long-term dopamine loss, striatonigral neurons lose their ability to respond to the neurotransmitter GABA (gamma-aminobutyric acid). This effect was not found with short-term dopamine loss.
These new findings open up possible ways to treat or prevent the dyskinesias. If such treatments were found, patients would probably seek to be treated early and improve their quality of life sooner.
Anders Borgkvist, Elizabeth M. Avegno, Minerva Y. Wong, Mazen A. Kheirbek, Mark S. Sonders, Rene Hen, David Sulzer. Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice. Neuron, 2015; 87 (5): 976 DOI: 10.1016/j.neuron.2015.08.022