DGLα is specifically localized to postsynaptic compartments (Katona et al., 2006; Lafourcade et al., 2007; Nomura et al., 2007; Yoshida et al., 2006). Whereas pharmacological studies inconsistently implicated DGLα in short-term synaptic plasticity, genetic deletion of DGLα indicates that this enzyme is required for Ca2+-dependent 2-AG production and short- and long-term eCB-dependent synaptic plasticity (Gao et al., 2010; Tanimura et al., 2010; Yoshino et al., 2011). Once synthesized, 2-AG travels backward

across the synapse; however, the precise mechanism by which this occurs is still unresolved. The primary degradative enzyme for 2-AG is Gemcitabine purchase monoacylglycerol lipase (MGL) (Blankman et al., 2007). MGL is found presynaptically (Gulyas et al., 2004; Ludányi et al., 2011), but its expression seems to be heterogeneous across synapses (Tanimura et al., 2012; Uchigashima et al., 2011; Yoshida et al., 2011). The postsynaptically localized serine hydrolase ABHD6 also catabolizes a small fraction of 2-AG (Marrs et al., 2010), suggesting functional redundancy that could help fine-tune this website 2-AG signaling. Nevertheless, it seems clear that MGL controls the duration and magnitude of 2-AG-mediated synaptic plasticity (Hashimotodani et al., 2007b; Pan et al., 2011; Schlosburg et al., 2010; Szabo et al., 2006). While 2-AG probably signals within 20 μm of

its site of origin (Chevaleyre and Castillo, 2004; Wilson and Nicoll, 2001), it would be useful to examine the relative contribution of MGL and ABHD6 to 2-AG diffusion. In contrast to synaptic 2-AG signaling, AEA synthesis and degradation seems more complex. Postsynaptic depolarization and intracellular Ca2+ influx support AEA production, but how this occurs is not fully understood (Di Marzo, 2011). AEA is in part synthesized by N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase-D (NAPE-PLD). However, alternative synthetic pathways exist (Okamoto et al., 2007). NAPE-PLD can be expressed

postsynaptically (Cristino et al., 2008) but was also observed on axonal membranes, in particular at CA3 mossy fiber terminals (Egertová et al., 2008; Nyilas et al., 2008), where AEA could locally modulate presynaptic function. AEA transport many across membranes might be facilitated by a lipophilic carrier protein (Beltramo et al., 1997; Fu et al., 2012; Hillard et al., 1997). This protein presumably supports AEA delivery to intracellular compartments where fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for AEA degradation, is localized (Gulyas et al., 2004). While 2-AG and AEA are hydrolyzed by MGL and FAAH, respectively, oxidizing enzymes like cyclooxygenase and lipoxygenase can also utilize these substrates (Vandevoorde and Lambert, 2007). Of interest, some of these eCB metabolites are biologically active (Nomura et al., 2011) and probably modulate synaptic function, a possibility that needs to be further investigated.