Dual Dopaminergic Regulation of Corticostriatal Plasticity by Cholinergic Interneurons and Indirect Pathway Medium Spiny Neurons

Endocannabinoid (eCB)-mediated long-term depression (LTD) requires dopamine (DA) D2 receptors (D2Rs) for eCB mobilization. The cellular locus of the D2Rs involved in LTD induction remains highly debated. We directly examined the role in LTD induction of D2Rs expressed by striatal cholinergic interneurons (Chls) and indirect pathway medium spiny neurons (iMSNs) using neuron-specific targeted deletion of D2Rs. Deletion of Chl-D2Rs (Chl-Drd2KO) impaired LTD induction in both subtypes of MSNs. LTD induction was restored in the Chl-Drd2KO mice by an M1-selective muscarinic acetylcholine receptor antagonist. In contrast, after the deletion of iMSN-D2Rs (iMSN-Drd2KO), LTD induction was intact in MSNs. Separate interrogation of direct pathway and iMSNs revealed a deficit in LTD induction only at synapses onto iMSNs that lack D2Rs. LTD induction in iMSNs was restored by D2R agonist application. Our findings suggest that Chl D2Rs strongly-modulate LTD induction in MSNs, with iMSN-D2Rs having a weaker, iMSN-specific, modulatory effect.