Endocannabinoids at the Synapse: Retrograde Signaling and Presynaptic Plasticity in the Brain

In the study of synaptic transmission, the field of endocannabinoid research is flowering. A wealth of recent findings has revealed critical molecular underpinnings of endocannabinoid generation and signal transduction, and the subcellular localization of these processes within neurons has been mapped with increasing detail. Sophisticated techniques of neuronal imaging and electrophysio- logical recording have combined to yield new insights into the timing and regulation of endocannabinoid signaling at synapses throughout the brain, and these discov- eries are beginning to influence models of synaptic computation and plasticity on a profound level. Triggered by membrane depolarization, intracellular Ca 2+ eleva- tion, and/or activation of G q/11 -coupled metabotropic receptors, postsynaptically released endocannabinoids act at presynaptic CB 1 receptors to mediate retrograde synaptic inhibition at both excitatory and inhibitory synapses, and on timescales that are either transient (on a scale of seconds) or long lasting. By dynamically modulating synapse reliability, synaptic suppression mediated by endocannabi- noids provides a means for postsynaptic neurons to "tune" the sensitivity of their synaptic inputs to afferent patterns of stimulation. This may in turn help to regu- late burst firing, or to generate or maintain synchronous membrane oscillations in interconnected neuronal populations. Endocannabinoid-dependent long-term synaptic depression (LTD) has also been recently demonstrated to underlie multi- ple forms of spike-timing-dependent plasticity (STDP) in the cerebral cortex, long thought to regulate the neuronal representation of sensory maps. In this chapter, I briefly survey updated concepts and mechanisms of endocannabinoid-mediated synaptic plasticity, and discuss the possible functional relevance of these processes to perception and behavior.