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The Journal of Neuroscience, April 4, 2007, 27(14):3663-3676; doi:10.1523/JNEUROSCI.0448-07.2007

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Cellular/Molecular
Subcellular Arrangement of Molecules for 2-Arachidonoyl-Glycerol-Mediated Retrograde Signaling and Its Physiological Contribution to Synaptic Modulation in the Striatum

Motokazu Uchigashima,^1 * Madoka Narushima,^2,3 * Masahiro Fukaya,¹ Istvan Katona,⁴ Masanobu Kano,² and Masahiko Watanabe¹

¹Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan, ²Department of Cellular Neuroscience, Graduate School of Medical Science, Osaka University, Suita 565-0871, Japan, ³Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-8666, Japan, and ⁴Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony utca 43, 1083 Budapest, Hungary.

Correspondence should be addressed to Masahiko Watanabe, Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan. Email: watamasa{at}med.hokudai.ac.jp

Endogenous cannabinoids (endocannabinoids) mediate retrograde signals for short- and long-term suppression of transmitter release at synapses of striatal medium spiny (MS) neurons. An endocannabinoid, 2-arachidonoyl-glycerol (2-AG), is synthesized from diacylglycerol (DAG) after membrane depolarization and Gq-coupled receptor activation. To understand 2-AG-mediated retrograde signaling in the striatum, we determined precise subcellular distributions of the synthetic enzyme of 2-AG, DAG lipase- (DAGL), and its upstream metabotropic glutamate receptor 5 (mGluR5) and muscarinic acetylcholine receptor 1 (M₁). DAGL, mGluR5, and M₁ were all richly distributed on the somatodendritic surface of MS neurons, but their subcellular distributions were different. Although mGluR5 and DAGL levels were highest in spines and accumulated in the perisynaptic region, M₁ level was lowest in spines and was rather excluded from the mGluR5-rich perisynaptic region. These subcellular arrangements suggest that mGluR5 and M₁ might differentially affect endocannabinoid-mediated, depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE) in MS neurons. Indeed, mGluR5 activation enhanced both DSI and DSE, whereas M₁ activation enhanced DSI only. Importantly, DSI, DSE, and receptor-driven endocannabinoid-mediated suppression were all abolished by the DAG lipase inhibitor tetrahydrolipstatin, indicating 2-AG as the major endocannabinoid mediating retrograde suppression at excitatory and inhibitory synapses of MS neurons. Accordingly, CB₁ cannabinoid receptor, the main target of 2-AG, was present at high levels on GABAergic axon terminals of MS neurons and parvalbumin-positive interneurons and at low levels on excitatory corticostriatal afferents. Thus, endocannabinoid signaling molecules are arranged to modulate the excitability of the MS neuron effectively depending on cortical activity and cholinergic tone as measured by mGluR5 and M₁ receptors, respectively.

Key words: endocannabinoid; CB₁; 2-arachidonoyl-glycerol (2-AG); diacylglycerol lipase (DAGL); mGluR5; muscarinic acetylcholine receptor M₁; immunohistochemistry; striatum; mouse

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Received Jan. 31, 2007; revised Feb. 22, 2007; accepted Feb. 23, 2007.

Correspondence should be addressed to Masahiko Watanabe, Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan. Email: watamasa{at}med.hokudai.ac.jp

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