Besides the classical cannabinoid

check details receptors (CB1R/CB2R), there is growing evidence that TRPV1 channels also participate in eCB signaling (De Petrocellis and Di Marzo, 2010; Pertwee et al., 2010). TRPV1, originally VR1 for vanilloid receptor type 1 (Caterina et al., 1997), is a polymodal transient receptor potential (TRP) ion channel largely expressed in afferent peripheral sensory neurons, where its activation regulates synaptic transmission associated with pain sensation (Caterina and Julius, 2001). Interestingly, TRPV1 can bind lipophilic substances, such as AEA (Di Marzo et al., 2002). Of note, AEA is a partial agonist at the CB1R but a full agonist at TRPV1 channels (Smart et al., 2000; Zygmunt et al., 1999). In addition to their expression in the periphery, TRPV1 channels have been found in the CNS (Cristino et al., 2006, 2008; Mezey et al., 2000; Puente et al., 2011; Roberts et al., 2004; Tóth et al., 2005) (but see Cavanaugh et al., 2011), where they

appear to regulate synaptic function. Recent studies revealed that AEA acting on TRPV1 mediates a postsynaptic form of LTD (Figure 3A). This TRPV1-LTD has been observed in dopamine receptor-2 (D2)-positive medium spiny neurons of the nucleus accumbens (Grueter et al., 2010), in dentate granule cells (Chávez et al., 2010), and in the bed nucleus of the stria terminalis (Puente et al., 2011). In each case, activation of mGluR5, presumably via PLC (Liu et al., 2008) VX-770 and Ca2+ release from intracellular stores, promotes the synthesis of AEA that activates TRPV1 channels. In addition, TRPV1-LTD relies on AMPA receptor (AMPAR) endocytosis. These findings are consistent with the notion that

AEA can act as an intracellular messenger (van der Stelt and Di Marzo, 2005) but differs from a presynaptic, TRPV1-dependent LTD at glutamatergic synapses onto CA1 hippocampal interneurons (Gibson et al., 2008). While CB1Rs mediate excitatory and inhibitory synaptic plasticity, whether brain TRPV1 channels mediate inhibitory synaptic plasticity is unknown. There is also evidence that TRPV1 localizes to neuronal intracellular compartments like the Dipeptidyl peptidase endoplasmic reticulum, trans-Golgi network, and perhaps even vesicles ( Dong et al., 2010). The functional significance of such receptors warrants further investigation. Nonretrograde eCB signaling has been observed in other contexts. Repetitive activation of a subtype of neocortical GABAergic interneuron triggers a CB1R-dependent postsynaptic hyperpolarization, which reduced its excitability (Figure 3B) (Bacci et al., 2004). This slow self-inhibition resulted from activity-dependent rises in intracellular Ca2+, mobilization of 2-AG, and activation of CB1Rs that couple to a G protein-coupled inwardly rectifying K+ channel (Bacci et al., 2004; Marinelli et al., 2008).