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SUMMARY The use of levodopa to manage Parkinson’s 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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