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The Journal of Neuroscience, May 24, 2006, 26(21):5628-5637; doi:10.1523/JNEUROSCI.0309-06.2006

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Development/Plasticity/Repair
Molecular Composition of the Endocannabinoid System at Glutamatergic Synapses

István Katona,¹ Gabriella M. Urbán,¹ Matthew Wallace,² Catherine Ledent,³ Kwang-Mook Jung,⁴ Daniele Piomelli,⁴ Ken Mackie,² and Tamás F. Freund¹

¹Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary, ²Department of Anesthesiology, University of Washington, Seattle, Washington 98195, ³Université Libre de Bruxelles, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, 1070 Bruxelles, Belgium, and ⁴Department of Pharmacology and Center for Drug Discovery, University of California, Irvine, Irvine, California 92697

Correspondence should be addressed to István Katona and Tamás F. Freund, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, H-1083 Budapest, Hungary. Email: katona{at}koki.hu and freund{at}koki.hu

Endocannabinoids play central roles in retrograde signaling at a wide variety of synapses throughout the CNS. Although several molecular components of the endocannabinoid system have been identified recently, their precise location and contribution to retrograde synaptic signaling is essentially unknown. Here we show, by using two independent riboprobes, that principal cell populations of the hippocampus express high levels of diacylglycerol lipase (DGL-), the enzyme involved in generation of the endocannabinoid 2-arachidonoyl-glycerol (2-AG). Immunostaining with two independent antibodies against DGL- revealed that this lipase was concentrated in heads of dendritic spines throughout the hippocampal formation. Furthermore, quantification of high-resolution immunoelectron microscopic data showed that this enzyme was highly compartmentalized into a wide perisynaptic annulus around the postsynaptic density of axospinous contacts but did not occur intrasynaptically. On the opposite side of the synapse, the axon terminals forming these excitatory contacts were found to be equipped with presynaptic CB₁ cannabinoid receptors. This precise anatomical positioning suggests that 2-AG produced by DGL- on spine heads may be involved in retrograde synaptic signaling at glutamatergic synapses, whereas CB₁ receptors located on the afferent terminals are in an ideal position to bind 2-AG and thereby adjust presynaptic glutamate release as a function of postsynaptic activity. We propose that this molecular composition of the endocannabinoid system may be a general feature of most glutamatergic synapses throughout the brain and may contribute to homosynaptic plasticity of excitatory synapses and to heterosynaptic plasticity between excitatory and inhibitory contacts.

Key words: mGluR5; DSI; GABA; interneuron; LTD; lipid; MGL

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Received Jan. 23, 2006; revised April 11, 2006; accepted April 13, 2006.

Correspondence should be addressed to István Katona and Tamás F. Freund, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, H-1083 Budapest, Hungary. Email: katona{at}koki.hu and freund{at}koki.hu

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