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bioRxiv · 10.1101/2025.05.16.654598

Repetitive Levodopa Treatment Drives Cell Type-Specific Striatal Adaptations Associated With Progressive Dyskinesia in Parkinsonian Mice

Paz, R. M.·Ryan, M. B.·Marcott, P. F.·Girasole, A. E.·Faryean, J.·Duong, V.·Sridhar, S.·Nelson, A. B.
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Abstract

The use of levodopa to manage Parkinsons disease (PD) symptoms leads to levodopa-induced dyskinesia (LID) and other motor fluctuations, which worsen with disease progression and repeated treatment. Aberrant activity of striatal D1- and D2-expressing medium spiny neurons (D1-/D2-MSNs) underlies LID, but the mechanisms driving its progression remain unclear. Using the 6-OHDA mouse model of PD/LID, we combined in vivo and ex vivo recordings to isolate the effect of repeated treatment in LID worsening and other motor fluctuation-related phenotypes. We found that LID worsening is linked to potentiation of levodopa-evoked responses in both D1-/D2-MSNs, independent of changes in dopamine release or MSN intrinsic excitability. Instead, strengthening of glutamatergic synapses onto D1-MSNs emerged as a key driver. Moreover, we found changes in D2-MSN activity that specifically influenced LID duration, potentially contributing to motor fluctuations, which paralleled a reduction in D2R sensitivity. These findings reveal striatal adaptations contributing to worsening of levodopa-related complications.

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Paz, R. M., Ryan, M. B., Marcott, P. F., Girasole, A. E., Faryean, J., Duong, V., Sridhar, S., Nelson, A. B.. 2025-05-21. Repetitive Levodopa Treatment Drives Cell Type-Specific Striatal Adaptations Associated With Progressive Dyskinesia in Parkinsonian Mice. https://doi.org/10.1101/2025.05.16.654598

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