title: RGS4 is required for dopaminergic control of striatal LTD and susceptibility to parkinsonian motor deficits.
abstract: 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 an effective nondopaminergic strategy for treating Parkinson's disease.
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Talia N
authors.initials: TN
authors.lastname: Lerner
authors.forename: Anatol C
authors.initials: AC
authors.lastname: Kreitzer
mesh_terms: D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D051379:Mice; D009474:Neurons / Q000378:metabolism; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism; D020710:RGS Proteins / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D063385:Cannabinoid Receptor Modulators; D020710:RGS Proteins; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; C098799:RGS4 protein; D016627:Oxidopamine; D019061:src-Family Kinases; D010739:Phospholipase D; D004298:Dopamine