Cell- and state-specific plasticity of striatal glutamatergic synapses is critical to the expression of levodopa-induced dyskinesia.

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Levodopa-induced dyskinesia (LID) is a debilitating complication of symptomatic therapy in Parkinson's disease. Although there is compelling evidence that striatal pathophysiology is a major driver of LID, the specific circuit mechanisms governing its expression remain obscure. To address this gap, molecular, cellular, and behavioral strategies were used to interrogate circuits in a mouse model of LID. These studies revealed that LID induction led to an upregulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) in indirect pathway spiny projection neurons (iSPNs), the emergence of "silent" glutamatergic synapses, and long-term synaptic potentiation. Knocking down the expression of Grin2b mRNA in iSPNs dramatically attenuated both the development and expression of LID without compromising the beneficial effects of levodopa on movement. Taken together, these studies demonstrate that dyskinesiogenic doses of levodopa trigger cell-specific synaptic adaptations that are necessary for the network pathophysiology underlying LID and suggest that targeting GluN2B-containing NMDARs in iSPNs could be therapeutically useful.

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