Dyskinesias in Parkinson’s disease are Caused by a Subgroup of Neurons

What's the science?

In Parkinson’s disease, dopamine neurons in the midbrain degenerate resulting in problems with body movement. A dopamine medication called levodopa can be very effective for improving symptoms, however, in some cases it causes involuntary movements called dyskinesias. We know that unwanted neural activity in brain regions such as the striatum, motor cortex and sensorimotor cortex may be involved, but the specific brain region and cells causing dyskinesias are not known. Recently in Neuron, Girasole and colleagues identify a subgroup of neurons responsible for dyskinesias.

How did they do it?

They first used a method called Targeted Recombination in Active Populations (TRAP) in transgenic (genetically modified) mice. TRAP allows certain proteins (acting as labels) to be expressed in active neurons (as opposed to inactive neurons). In mice with levodopa-induced dyskinesias, they identified neurons that were active during the dyskinesias compared to control mice. Second, they then used optogenetics: Controlling neuron activation by shining light on genetically modified neurons of interest. This allowed them to inhibit and activate these specific neurons in the mice to see if they played a causal role in dyskinesias.

What did they find?

Only neurons in the striatum were significantly more active during dyskinesias compared to control mice. When examining these neurons more closely, they found that most of the active neurons were medium spiny neurons (a specific cell type of neuron found in the striatum) that were part of the 'direct pathway', an inhibitory pathway involved in motor function that is defective in Parkinson’s disease. When these neurons were inhibited with optogenetics, the dyskinesias were reduced. Inhibiting the activity of neurons in the motor or sensorimotor cortices did not reduce dyskinesias, demonstrating a causal role for striatal neurons in producing medication-induced dyskinesias.

Images are generated by Life Science Databases(LSDB).,  Striatum , colour by BrainPost,  CC BY-SA 1.0

Images are generated by Life Science Databases(LSDB)., Striatum, colour by BrainPost, CC BY-SA 1.0

What's the impact?

This is the first study to identify the neurons within the striatum that cause dyskinesias in mice. Dyskinesias are a detrimental side effect of levodopa in Parkinson’s disease and can be debilitating to patients who experience them. Understanding which neurons cause dyskinesias brings us one step closer to finding a way to treat them.

Reach out to study author Ally Girasole on Twitter @AllyGirasole

A. E. Girasole et al., A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia. Neuron. 97, 1–9 (2018). Access the original scientific publication here.