Plasticity of excitatory synapses onto striatal projection neurons (MSNs) has the potential to regulate motor function by setting the gain on signals driving both direct- and indirect-pathway basal ganglia circuits. Endocannabinoid-dependent long-term depression (eCB-LTD) is the best characterized form of striatal plasticity, but the mechanisms governing its normal regulation and pathological dysregulation are not well understood. We characterized two distinct signaling pathways mediating eCB production in striatal indirect-pathway MSNs and found that both pathways were modulated by dopamine D2 and adenosine A2A receptors, acting through cAMP/PKA. We identified regulator of G protein signaling 4 (RGS4) as a key link between D2/A2A signaling and eCB mobilization pathways. In contrast to wild-type mice, RGS4 -/- mice exhibited normal eCB-LTD after dopamine depletion and were significantly less impaired in the 6-OHDA model of Parkinson's disease. Taken together, these results suggest that inhibition of RGS4 may be aneffective nondopaminergic strategy for treating Parkinson's disease. Video Abstract: Endocannabinoid-dependent LTD is the best characterized form of striatal plasticity, providing potential regulation of basal ganglia function. Lerner and Kreitzer show that regulator of G protein signaling 4 links dopamine D2 and adenosine A2A receptor signaling and endocannabinoid mobilization pathways to regulate plasticity at these synapses.
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