Endocannabinoid signaling and long-term synaptic plasticity

Abstract

Endocannabinoids (eCBs) are key activity-dependent signals regulating synaptic transmission throughout the central nervous system. Accordingly, eCBs are involved in neural functions ranging from feeding homeostasis to cognition. There is great interest in understanding how exogenous (e.g., cannabis) and endogenous cannabinoids affect behavior. Because behavioral adaptations are widely considered to rely on changes in synaptic strength, the prevalence of eCB-mediated long-term depression (eCB-LTD) at synapses throughout the brain merits close attention. The induction and expression of eCB-LTD, although remarkably similar at various synapses, are controlled by an array of regulatory influences that we are just beginning to uncover. This complexity endows eCB-LTD with important computational properties, such as coincidence detection and input specificity, critical for higher CNS functions like learning and memory. In this article, we review the major molecular and cellular mechanisms underlying eCB-LTD, as well as the potential physiological relevance of this widespread form of synaptic plasticity.

Figure 1. Schematic summary of the eCB-LTD induction mechanism

One of the most common initial steps of induction is the activation of postsynaptic group I metabotropic glutamate receptors (mGluR-I), following repetitive activation of excitatory inputs. These receptors couple to Phopholipase C (PLC) via Gα_q/11 subunits and promote diacylglycerol (DAG) formation (from Phosphatdylinositol, PI), which is then converted into the eCB 2-arachidonoylglycerol (2-AG) by Diacylglycerol Lipase (DGL). 2-AG is then released from the postsynaptic neuron by a mechanism that presumably requires an eCB membrane transporter (EMT), and binds presynaptic CB1Rs. Postsynaptic Ca²⁺ can contribute to eCB mobilization either by stimulating PLC, or in a PLC-independent, uncharacterized manner. This Ca²⁺ rise can be through voltage-dependent Ca2+channels (VDCC) actived by action potentials (e.g. during spike timing-dependent protocols), NMDARs, or released from the Endoplasmic Reticulum (ER), e.g. by the PLC product, inositol 1,4,5-trisposphate (IP3). In some synapses, induction of eCB-LTD by “afferent-only” stimulation protocols can occur independently of postsynaptic Ca2+. At the presynaptic terminal, the CB1R inhibits adenylyl cyclase (AC) via Gα_i/o, reducing PKA activity. Induction of eCB-LTD may also require a presynaptic Ca²⁺ rise through presynaptic VDCCs, NMDARs (not shown) or release from Ca²⁺ internal stores. Activation of the Ca²⁺-sensitive phosphatase calcineurin (CaN), in conjunction with the reduction in PKA activity, shifts the kinase/phosphatase activity balance, thereby promoting dephosphorylation of a presynaptic target (T) that mediates a long-lasting reduction of transmitter release. For clarity, eCB-LTD mediated by AEA is not shown.

Figure 2. Potential mechanisms of associativity involved in eCB-LTD induction

Postsynaptic compartment (left): the postsynaptic neuron can integrate action potential firing (which promotes Ca²⁺ rise via VDCCs) and synaptic release of glutamate (which activates mGluR-I) to facilitate eCB mobilization and eCB-LTD induction. Other Ca²⁺ sources (e.g. NMDARs and Ca²⁺ internal stores) could also contribute. In this model, PLC operates as a coincidence detector (61). Presynaptic compartment (right): the presynaptic terminal can also integrate two signals, eCBs (which activate presynaptic CB1Rs) and presynaptic firing (which promotes a Ca²⁺ rise via VDCCs and NMDARs). Ca²⁺ stores (endoplasmic reticulum, ER) may also contribute to this process. The presynaptic NMDAR may operate as a coincidence detector during a brief time window (26). In addition, the activity-dependent Ca²⁺ rise that occurs during minutes of CB1R activation likely promotes dephosphorylation of a presynaptic target downstream of the CB1R, the latter of which is an essential step for eCB-LTD induction (78).