Endocannabinoid-Mediated Control of Synaptic Transmission, Masanobu KANO et al., 2009

Endocannabinoid-Mediated Control of Synaptic Transmission


I. Introduction 310
II. Cannabinoid Receptors 311
A. CB1 receptor 311
B. CB2 receptor 315
C. “CB3” receptor 315
D. TRPV1 receptor 317
E. GPR55 receptor 317
III. CB1 Receptor Signaling 317
A. Intracellular signaling pathways 317
B. Suppression of transmitter release 318
C. Morphological changes 318
IV. Biochemistry of Endocannabinoids 318
A. Endocannabinoids 318
B. Biosynthesis of anandamide 319
C. Biosynthesis of 2-AG 320
D. Degradation of endocannabinoids 321
E. Endocannabinoid transport 321
F. Lipid raft 322
V. Endocannabinoid-Mediated Short-Term Depression 322
A. Endocannabinoid as a retrograde messenger 322
B. eCB-STD in various brain regions 324
C. Mechanisms of ecb-std 334
VI. Endocannabinoid-Mediated Long-Term Depression 341
A. eCB-LTD in various brain regions 341
B. Mechanisms of endocannabinoid release in eCB-LTD 347
C. Presynaptic mechanisms of eCB-LTD 347
VII. Other Properties of Endocannabinoid Signaling 348
A. Modulation of endocannabinoid-independent synaptic plasticity 348
B. Regulation of excitability 348
C. Basal activity of endocannabinoid signaling 348
D. Plasticity of endocannabinoid signaling 349
E. Actions of endocannabinoid-derived oxygenated products by COX-2 350
F. Contribution of astrocytes to endocannabinoid signaling 350
VIII. Subcellular Distributions of Endocannabinoid Signaling Molecules 350
A. CB1 receptor 351
B. Gq/11 protein-coupled receptors 353
C. Gq protein -subunit 356
D. Phospholipase C 356
E. Diacylglycerol lipase 357
F. N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D 357
G. Monoacylglycerol lipase 357
H. Fatty acid amide hydrolase 358
I. Cyclooxygenase-2 358
J. Organization of 2-AG signaling molecules in the cerebellum, hippocampus, and striatum 358
IX. Physiological Roles of the Endocannabinoid System 359
A. Learning and memory 359
B. Anxiety 361
C. Depression 362

D. Addiction 362
E. Appetite and feeding behavior 363
F. Pain 363
G. Neuroprotection 364
X. Conclusions 365


The discovery of cannabinoid receptors and subsequent identification of their endogenous ligands (endocannabinoids) in early 1990s have greatly accelerated research on cannabinoid actions in the brain. Then, the discovery in 2001 that endocannabinoids mediate retrograde synaptic signaling has opened up a new era for cannabinoid research and also established a new concept how diffusible messengers modulate synaptic efficacy and neural activity. The last 7 years have witnessed remarkable advances in our understanding of the endocannabinoid system. It is now well accepted that endocannabinoids are released from postsynaptic neurons, activate presynaptic cannabinoid CB1 receptors, and cause transient and long-lasting reduction of neurotransmitter release. In this review, we aim to integrate our current understanding of functions of the endocannabinoid system, especially focusing on the control of synaptic transmission in the brain. We summarize recent electrophysiological studies carried out on synapses of various brain regions and discuss how synaptic transmission is regulated by endocannabinoid signaling. Then we refer to recent anatomical studies on subcellular distribution of the molecules involved in endocannabinoid signaling and discuss how these signaling molecules are arranged around synapses. In addition, we make a brief overview of studies on cannabinoid receptors and their intracellular signaling, biochemical studies on endocannabinoid metabolism, and behavioral studies on the roles of the endocannabinoid system in various aspects of neural functions.