Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses

Marijuana affects brain function primarily by activating the G-protein-coup led cannabinoid receptor-1 (CB1)(1-3), which is expressed throughout the br ain at high levels'. Two endogenous lipids, anandamide and 2-arachidonylgly cerol (2-AG), have been identified as CB1 ligands(5,6). Depolarized hippoca mpal neurons rapidly release both anandamide and 2-AG in a Ca2+-dependent m anner(6-8). In the hippocampus, CB1 is expressed mainly by GABA (gamma -ami nobutyric acid)-mediated inhibitory interneurons, where CB1 clusters on the axon terminal(9-11). A synthetic CB1 agonist depresses GABA release from h ippocampal slices(10,12) These findings indicate that the function of endog enous cannabinoids released by depolarized hippocampal neurons might be to downregulate GABA release. Here we show that the transient suppression of G ABA-mediated transmission that follows depolarization of hippocampal pyrami dal neurons(13) is mediated by retrograde signalling through release of end ogenous cannabinoids. Signalling by the endocannabinoid system thus represe nts a mechanism by which neurons fan communicate backwards across synapses to modulate their inputs.