However, there is also evidence suggesting that eCBs signal in a nonretrograde or autocrine manner, in which they can modulate neural function and synaptic transmission by engaging transient receptor potential vanilloid receptor type 1 (TRPV1) and also CB1Rs located on or within the postsynaptic cell (Figure 1B). Finally, recent studies indicate that eCBs can signal via astrocytes to indirectly modulate presynaptic or postsynaptic function (Figure 1C). This Review aims to highlight
the emerging mechanistic diversity of synaptic eCB signaling. The first demonstration of retrograde eCB signaling came from the discovery that eCBs mediate forms of short-term synaptic plasticity known as depolarization-induced suppression of inhibition (DSI) (Ohno-Shosaku et al., VE-821 concentration 2001; Wilson and Nicoll, 2001) and depolarization-induced
suppression of excitation (DSE) (Kreitzer and Regehr, 2001). Shortly after it was shown that eCBs also mediate presynaptic forms of long-term depression (eCB-LTD) at both excitatory (Gerdeman et al., 2002; Robbe et al., 2002) and inhibitory (Chevaleyre and Castillo, 2003; Marsicano et al., 2002) synapses. eCBs have since emerged as the best characterized retrograde messengers (Regehr et al., 2009), with numerous examples of short- and long-term forms of synaptic plasticity reported throughout the brain (Heifets and Castillo, 2009; Kano et al., 2009). CB1/CB2 receptors are Gi/o protein-coupled receptors that mediate RAD001 ic50 almost all effects of exogenous and endogenous cannabinoids. CB1Rs are one of the most widely expressed GPCRs in
the brain (Herkenham et al., 1990). Their localization to neuronal terminals (Katona et al., 1999, 2006) strongly suggests that CB1Rs play important roles in regulating synaptic function. Indeed, CB1R activation inhibits neurotransmitter release at synapses through two main mechanisms (Figure 2) (Chevaleyre et al., 2006; Freund et al., 2003; Kano et al., 2009). For short-term plasticity, in which CB1Rs are activated for a few seconds, the mechanism involves direct G protein-dependent (likely via the βγ subunits) inhibition of presynaptic Non-specific serine/threonine protein kinase Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) (Brown et al., 2003; Kreitzer and Regehr, 2001; Wilson et al., 2001). For long-term plasticity, the predominant mechanism requires inhibition of adenylyl cyclase and downregulation of the cAMP/PKA pathway via the αi/o limb (Chevaleyre et al., 2006; Heifets and Castillo, 2009). Moreover, CB1Rs only need to be engaged during the induction, but not expression, phase of eCB-LTD. Induction also requires combined presynaptic firing with CB1R activation, thereby providing a mechanism for input specificity; that is, only active synapses detecting eCBs express long-term plasticity (Heifets et al., 2008; Singla et al., 2007). The expression mechanism for eCB-LTD may involve presynaptic proteins Rab3B/RIM1α (Chevaleyre et al., 2007; Tsetsenis et al.