The endocannabinoid (eCB) signaling system plays a key role in short-term and long-term synaptic plasticity in brain regions involved in various neural functions ranging from action selection to appetite control. This review will explore the role of eCBs in shaping neural circuit function to regulate behaviors. In particular, we will discuss the behavioral consequences of eCB mediated long-term synaptic plasticity in different brain regions. This review brings together evidence from in vitro and ex vivo studies and points out the need for more in vivo studies.

These data suggest a role for 2-AG deficiency in social deficits and repetitive behavior, and they demonstrate a key role for 2-AG in regulating striatal direct-pathway MSNs.

SUMMARY Endocannabinoid (eCB)-mediated long-term depres-sion (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 induc-tion of D2Rs expressed by striatal cholinergic inter-neurons (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 syn-apses 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.