Endocannabinoid signaling and synaptic function

Abstract

Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a nonretrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. In this Review, we focus on new advances in synaptic endocannabinoid signaling in the mammalian brain. The emerging picture not only reinforces endocannabinoids as potent regulators of synaptic function but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought.

Figure 1. Endocannabinoid signaling at the synapse

A, Retrograde endocannabinoid (eCB) signaling. eCBs are mobilized from postsynaptic neurons and target presynaptic cannabinoid type-1 receptors (CB₁Rs) to suppress neurotransmitter release. B, Non-retrograde eCB signaling. eCBs produced in postsynaptic neurons activate postsynaptic CB₁Rs or transient receptor potential vanilloid-type 1 (TRPV1) channels. C, Neuron-astrocyte eCB signaling. eCBs released from postsynaptic neurons stimulate astrocytic CB₁Rs, thereby triggering gliotransmission. Glu, glutamate.

Figure 2. Molecular mechanisms underlying endocannabinoid-mediated short- and long-term synaptic plasticity

A, Short-term depression. Postsynaptic activity triggers Ca²⁺ influx via voltage-gated Ca²⁺ channels (VGCCs). Other Ca²⁺ sources, like NMDARs and internal stores, may contribute. Ca²⁺ promotes diacylglycerol lipase (DGLα)-mediated eCB production by an unknown mechanism. Presynaptic activity can also lead to eCB mobilization by activating postsynaptic group-I metabotropic glutamate receptors (I-mGluRs). Phospholipase-Cβ (PLCβ) can now act as a coincidence detector integrating pre- and postsynaptic activity. DGLα promotes 2-arachidonoylglycerol (2-AG) release which retrogradely targets presynaptic CB₁Rs, and the βγ subunits likely couple to presynaptic VGCCs to reduce neurotransmitter release. B, eCB-mediated excitatory long-term depression (LTD) and inhibitory LTD (iLTD). Patterned presynaptic stimulation releases Glu which activates postsynaptic mGluRs coupled to PLCβ and DGLα. 2-AG homosynaptically targets CB₁Rs localized to excitatory terminals and heterosynaptically engages CB₁Rs at inhibitory terminals. A G_αi/o-dependent reduction in adenylyl cyclase (AC) and protein kinase A (PKA) activity suppresses transmitter release. At inhibitory synapses, decreased PKA activity, in conjunction with activation of the Ca²⁺-sensitive phosphatase calcineurin (CaN), shifts the phosphorylation status of an unidentified presynaptic target (T) required for iLTD. The active zone protein RIM1α and the vesicle-associated protein Rab3B are also necessary for iLTD. Induction of eCB-LTD may require presynaptic Ca²⁺ rise through VGCCs, NMDARs, or internal stores (not shown). Dashed lines indicate putative pathways.

Figure 3. Non-retrograde eCB signaling

A, Mechanism underlying postsynaptic TRPV1-LTD. Presynaptic activity releases glutamate that stimulates mGluR5. Postsynaptic depolarization may also be required. mGluR5 couples to anandamide (AEA) production which activates TRPV1, leading to enhanced Ca²⁺ signaling. Ca²⁺ engages calcineurin/dynamin (CaN/Dyn), causing AMPA receptor (AMPAR) endocytosis and LTD. IC, intracellular compartment. N. Accumbens, nucleus accumbens; BNST, bed nucleus of the stria terminalis. B, Mechanism responsible for slow-self inhibition (autocrine signaling). Postsynaptic activity-induced Ca²⁺ elevation facilitates 2-AG production. 2-AG activates postsynaptic CB₁Rs that signal to a G protein-coupled inwardly rectifying K+ (GIRK) channel to hyperpolarize the membrane potential and inhibit neuronal firing. Dashed lines indicate putative pathways.

Figure 4. Astrocytic CB₁Rs modulation of synaptic transmission

A, Short-term plasticity. Postsynaptic neuronal activity leads to eCB release. eCBs target G_q/11-coupled CB₁Rs localized to astrocytes. As a result, PLC activity facilitates astrocytic Ca²⁺ signaling. Glu released from the astrocyte activates presynaptic mGluR1s to potentiate release and postsynaptic NMDARs to trigger a slow inward current. B, Spike-timing-dependent LTD. Repetitive pairings of post-before-pre synaptic activity mobilizes eCBs through the neuronal PLCβ-coincidence detection mechanism. Released eCB stimulates astrocytic CB₁Rs, leading to Ca²⁺ signaling. Astrocyte-mediated Glu release activates presynaptic NMDARs to depress release.