This modulation of eCB-LTD by D2 and A2A receptors requires RGS4, which is phosphorylated by PKA (Huang et al., 2007) and inhibits mGluR-Gq signaling (Saugstad et al., 1998). RGS4 is therefore a key link between dopamine signaling, synaptic plasticity, and motor behavior, and may be a promising non-dopaminergic target for modulating basal ganglia circuitry. Our finding of two distinct forms of eCB-LTD (HFS-LTD and LFS-LTD) in the same cell type both clarifies previous findings and raises new questions. Our data agree with previous studies indicating Ceritinib molecular weight that AEA is the eCB

mediating HFS-LTD while highlighting the importance of PLD for its production (Ade and Lovinger, 2007 and Kreitzer and Malenka, 2007). However, other studies of striatal eCB-LTD have indicated that 2-AG is the eCB that mediates striatal eCB-LTD (Fino et al., 2010 and Lerner et al., 2010). Indeed, we confirm that 2-AG can also mediate eCB-LTD, given KRX-0401 supplier the right stimulation frequency and duration, thus helping to

resolve some of the apparent conflicts in the literature. Additionally, our LFS-LTD data fit well with a previous study of striatal LTD using low-frequency stimulation (Ronesi and Lovinger, 2005), which until now was difficult to reconcile with studies of HFS-LTD. Like this LTD, which was induced by 5 min of continuous 10 Hz stimulation, our LFS-LTD is prevented by blockers of CB1 receptors and D2 receptors, but not by L-VGCC blockers or by calcium chelation with BAPTA. Together with our data, these findings demonstrate that eCB-LTD can be calcium-independent, most likely because PLCβ can be sufficiently activated by prolonged group I mGluR activation alone. Both HFS-LTD and LFS-LTD are

modulated by dopamine D2 receptors and adenosine A2A receptors and this modulation of LTD appears to be important for regulating motor function (Kreitzer and Malenka, 2007 and Lerner et al., 2010). Here Phosphatidylinositol diacylglycerol-lyase we provide the first evidence of a specific mechanism by which D2 and A2A receptor modulation of LTD occurs, via cAMP/PKA mediated regulation of RGS4 activity. While our experiments argue that D2 and A2A receptors regulate LTD induction mainly via their downstream signaling pathways, we cannot rule out a role for physical interactions of D2 and A2A receptors in the membrane, which have been reported (for review see Fuxe et al., 2005 and Fuxe et al., 2007), though not studied in the context of LTD. D2 and A2A receptors appear to regulate cAMP accumulation in MSNs primarily by acting on adenylyl cyclase 5 (AC5), a striatal-enriched form of adenylyl cyclase, since mice lacking AC5 have impaired striatal synaptic plasticity.