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 non-retrograde 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. Synaptic endocannabinoid signaling is thus mechanistically more complex and diverse than originally thought. In this review, we focus on new advances in endocannabinoid signaling and highlight their role as potent regulators of synaptic function in the mammalian brain.

Changes in synaptic efficacy are thought to be crucial to experience-dependent modifications of neural function. The diversity of mechanisms underlying these changes is far greater than previously expected. In the last five years, a new class of use-dependent synaptic plasticity that requires retrograde signaling by endocannabinoids (eCB) and presynaptic CB1 receptor activation has been identified in several brain structures. eCB-mediated plasticity encompasses many forms of transient and long-lasting synaptic depression and is found at both excitatory and inhibitory synapses. In addition, eCBs can modify the inducibility of non-eCB-mediated forms of plasticity. Thus, the eCB system is emerging as a major player in synaptic plasticity. Given the wide distribution of CB1 receptors in the CNS, the list of brain structures and synapses expressing eCB-mediated plasticity is likely to expand.

Neurotransmitters are released by synaptic vesicle fusion at the active zone. The active zone of a synapse mediates Ca2+-triggered neurotransmitter release, and integrates presynaptic signals in regulating this release. Much is known about the structure of active zones and synaptic vesicles, but the functional relation between their components is poorly understood. Here we show that RIM1alpha, an active zone protein that was identified as a putative effector for the synaptic vesicle protein Rab3A, interacts with several active zone molecules, including Munc13-1 (ref. 6) and alpha-liprins, to form a protein scaffold in the presynaptic nerve terminal. Abolishing the expression of RIM1alpha in mice shows that RIM1alpha is essential for maintaining normal probability of neurotransmitter release, and for regulating release during short-term synaptic plasticity. These data indicate that RIM1alpha has a central function in integrating active zone proteins and synaptic vesicles into a molecular scaffold that controls neurotransmitter release.

Glutamate, the neurotransmitter at most excitatory synapses in the brain, activates a variety of receptor subtypes that can broadly be divided into ionotropic (ligand-gated ion channels) and metabotropic (G-protein-coupled) receptors. Ionotropic receptors mediate fast excitatory synaptic transmission, and based on pharmacological and molecular biological studies are divided into NMDA and non-NMDA subtypes. The non-NMDA receptor group is further divided into AMPA and kainate subtypes. Virtually all fast excitatory postsynaptic currents studied so far in the central nervous system are mediated by the AMPA and NMDA subtypes of receptors. Surprisingly, despite extensive analysis of their structure, biophysical properties and anatomical distribution, a synaptic role for kainate receptors in the brain has not been found. Here we report that repetitive activation of the hippocampal mossy fibre pathway, which is associated with high-affinity kainate binding and many of the kainate receptor subtypes, generates a slow excitatory synaptic current with all of the properties expected of a kainate receptor. This activity-dependent synaptic current greatly augments the excitatory drive of CA3 pyramidal cells.