D2R signaling in striatal spiny neurons modulates L-DOPA induced dyskinesia

Degeneration of dopaminergic neurons leads to Parkinson’s disease (PD), characterized by reduced levels of striatal dopamine (DA) and impaired voluntary movements. DA replacement is achieved by levodopa treatment which in long-term causes involuntary movements or dyskinesia. Dyskinesia is linked to the pulsatile activation of D1 receptors of the striatal medium spiny neurons (MSNs) forming the direct output pathway (dMSNs). The contribution of DA stimulation of D2R in MSNs of the indirect pathway (iMSNs) is less clear. Using the 6-hydroxydopamine model of PD, here we show that loss of DA-mediated inhibition of these neurons intensifies levodopa-induced dyskinesia (LID) leading to reprogramming of striatal gene expression. We propose that the motor impairments characteristic of PD and of its therapy are critically dependent on D2R-mediated iMSNs activity. D2R signaling not only filters inputs to the striatum but also indirectly regulates dMSNs mediated responses. [Display omitted] •D2RKO in iMSNs increases L-DOPA-induced dyskinesia (LID)•D2R signaling in iMSNs inhibits striatal gene and PD-associated genes•Unopposed M1R signaling is responsible for the increased LID in iMSN-D2RKO mice•Simultaneous modulation of M1R and M4R signaling on MSNs drastically reduces LID Biological sciences; Neuroscience; Behavioral neuroscience; Transcriptomics