Date of Degree
PhD (Doctor of Philosophy)
Levodopa-induced dyskinesias (LIDs) are abnormal involuntary movements that limit the effectiveness of treatments for Parkinson’s disease. Although dyskinesias involve the striatum, it is unclear how striatal neurons are involved in dyskinetic movements. Here we record from striatal neurons in mice during levodopa-induced axial dyskinesias. We developed an automated 3-dimensional motion tracking system to capture the development of axial dyskinesias at ~10 ms resolution, and correlated these movements with neuronal activity of striatal medium spiny neurons and fast spiking interneurons. The average firing rate of medium spiny neurons increased as axial dyskinesias developed, and both medium spiny neurons and fast spiking interneurons were modulated around axial dyskinesias. We also found that delta field potential power increased in the striatum with dyskinesia, and that this increased delta power coupled with striatal neurons.
Secondly, we studied the role of the two main types of dopamine receptors. We pharmacologically inhibited either the D1 or D2 receptors while recording from neuronal ensembles in the striatum and measuring LIDs in high temporal resolution. We found that inhibiting the D1, but not the D2, receptor led to a decrease in axial dyskinesias. Interestingly, both types of antagonist attenuated the strong modulation of MSNs around axial dyskinesias when compared to levodopa alone. These results suggest that LIDs are modulated through activity in D1-MSNs.
Lastly, we selectively targeted the D1 receptor expressing neurons (D1-MSNs) with optogenetics. With this technique, we can specifically activate or inhibit certain neuronal populations. We found that stimulating the D1-MSNs led to dyskinetic events only after levodopa priming. However, inhibiting these neurons was not sufficient to attenuate dyskinesias following levodopa administration. We also found that putative D1-MSNs are more strongly modulated around axial dyskinesias than other MSNs.
Together, our findings provide novel insight into how striatal networks change as LIDs develop, and suggest that increased medium spiny neuron firing, that D1-MSNs are strongly modulated around LIDs, and that D1-MSN activity is sufficient to drive dyskinesias. These data could help clarify the role of the striatum in the pathogenesis of dyskinesias in Parkinson’s disease.
xii, 85 pages
Includes bibliographical references (pages 70-84).
Copyright © 2017 Stephanie Lorraine Alberico