The Neuroscientist 18(2) 119 –132 © The Author(s) 2012 Reprints and permission: http://www. sagepub.com/journalsPermissions.nav DOI: 10.1177/1073858410397377 http://nro.sagepub.com

Review

Historical Overview

Marijuana, a derivative of Cannabis sativa, has been used for thousands of years for its therapeutic and mood- or perception-altering properties. In 1964, ?9- tetrahydrocannabinol (?9-THC) was identified as the main psychoactive component of marijuana. In the 1990s, two types of receptors for ?9-THC, CB

1 (CB

1 R) and CB

2 can-

nabinoid receptors (CB 2 R), and two endogenous ligands

(endocannabinoids), N-arachidonylethanolamide (anan- damide) and 2-arachidonylglycerol (2-AG), were found.

In 2001, endocannabinoids were discovered to function as retrograde messengers at synapses in the hippocampus and cerebellum. It is now widely accepted that endocan- nabinoids are released from postsynaptic neurons upon postsynaptic depolarization and/or receptor activation and act on presynaptic CB

1 R to induce transient suppression of

transmitter release (endocannabinoid-mediated short-term depression [eCB-STD]). In 2002, endocannabinoid- mediated long-term depression (eCB-LTD) was found in the striatum and nucleus accumbens. Later studies have confirmed that eCB-STD and eCB-LTD can be induced at

various types of synapses throughout the brain. Anatomical studies have revealed that the molecular elements of retro- grade endocannabinoid signaling are arranged around syn- apses in functionally relevant manners. Behavioral studies using CB

1 R agonists and antagonists or CB

1 R knockout

mice have demonstrated that the endocannabinoid system is involved in various aspects of neural functions, including learning, drug addiction, feeding behavior, and analgesia.

Recent studies have revealed that the endocannabinoid system has more diverse functional roles than previously thought and is up- or down-regulated in response to

397377 NRO18210.1177/1073858410397377 Ohno-Shosaku and othersThe Neuroscientist

1Division of Health Science, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan 2Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Corresponding Author: Masanobu Kano, Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan Email: mkano-tky@m.u-tokyo.ac.jp

Endocannabinoids and Retrograde Modulation of Synaptic Transmission

Takako Ohno-Shosaku1, Asami Tanimura2, Yuki Hashimotodani2, and Masanobu Kano2

Abstract

Since the first reports of endocannabinoid-mediated retrograde signaling in 2001, great advances have been made toward understanding the molecular basis and functions of the endocannabinoid system. Electrophysiological studies have revealed that the endocannabinoid system is functional at various types of synapses throughout the brain. Basic mechanisms have been clarified as to how endocannabinoids are produced and released from postsynaptic neurons and regulate neurotransmitter release through activating presynaptic cannabinoid CB

1 receptors, although there remain

unsolved questions and some discrepancies. In addition to this major function, recent studies suggest diverse functions of endocannabinoids, including control of other endocannabinoid-independent forms of synaptic plasticity, regulation of neuronal excitability, stimulation of glia-neuron interaction, and induction of CB

1 R-independent plasticity. Using recently

developed pharmacological and genetic tools, behavioral studies have elucidated the roles of the endocannabinoid system in various aspects of neural functions. In this review, we make a brief overview of molecular mechanisms underlying the endocannabinoid-mediated synaptic modulation and also summarize recent findings, which shed new light on a diversity of functional roles of endocannabinoids.

Keywords

endocannabinoid, retrograde signaling, CB 1 , 2-arachidonylglycerol, diacylglycerol lipase, synapse, marijuana, short-term

depression, long-term depression

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120 The Neuroscientist 18(2)

various factors. In parallel, efficient pharmacological and genetic tools have been developed, facilitating the func- tional investigation of 2-AG and anandamide signaling pathways. This review provides our current understand- ing of the endocannabinoid system, with particular emphasis on molecular mechanisms of eCB-STD/LTD and recent topics. Because of limited space, only a lim- ited number of references are included. For more infor- mation about original papers, several excellent reviews are available (Alger 2002; Chevaleyre and others 2006; Freund and others 2003; Heifets and Castillo 2009; Kano and others 2009; Piomelli 2003).essay