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The Journal of Neuroscience, August 23, 2006, 26(34):8829-8837; doi:10.1523/JNEUROSCI.1236-06.2006

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Behavioral/Systems/Cognitive
Endogenous Cannabinoid Signaling through the CB₁ Receptor Is Essential for Cerebellum-Dependent Discrete Motor Learning

Yasushi Kishimoto^1,2 and Masanobu Kano^1,2

¹Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan, and ²Department of Cellular Neurophysiology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan

Correspondence should be addressed to Masanobu Kano, Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Japan. Email: mkano{at}cns.med.osaka-u.ac.jp

Cannabinoids exert their psychomotor actions through the CB₁ cannabinoid receptor in the brain. Genetic deletion of CB₁ in mice causes various symptoms, including changes in locomotor activity, increased ring catalepsy, supraspinal hypoalgesia, and impaired memory extinction. Although the cerebellar cortex contains the highest level of CB₁, severe cerebellum-related functional deficits have not been reported in CB₁ knock-out mice. To clarify the roles of CB₁ in cerebellar function, we subjected CB₁ knock-out mice to a delay version of classical eyeblink conditioning. This paradigm is a test for cerebellum-dependent discrete motor learning, in which conditioned stimulus (CS) (352 ms tone) and unconditioned stimulus (US) (100 ms periorbital electrical shock) are coterminated. We found that delay eyeblink conditioning performance was severely impaired in CB₁ knock-out mice. In contrast, they exhibited normal performance in a trace version of eyeblink conditioning with 500 ms stimulus-free interval intervened between the CS offset and the US onset. This paradigm is a test for hippocampus-dependent associative learning. Sensitivity of CB₁ knock-out mice to CS or US was normal, suggesting that impaired delay eyeblink conditioning is attributable to defects in association of responses to CS and US. We also found that intraperitoneal injection of the CB₁ antagonist SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole carboxamide] to wild-type mice caused severe impairment in acquisition but not extinction of delay eyeblink conditioning. SR141716A treatment had no effect on trace eyeblink conditioning with a 500 or 750 ms trace interval. These results indicate that endogenous cannabinoid signaling through CB₁ is essential for cerebellum-dependent discrete motor learning, especially for its acquisition.

Key words: CB₁ cannabinoid receptor; endocannabinoid; delay eyeblink conditioning; trace eyeblink conditioning; motor learning; associative learning; knock-out mice; cerebellum; Purkinje cell

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Received March 22, 2006; revised July 3, 2006; accepted July 19, 2006.

Correspondence should be addressed to Masanobu Kano, Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Japan. Email: mkano{at}cns.med.osaka-u.ac.jp

This article has been cited by other articles:

				M. Kano, T. Ohno-Shosaku, Y. Hashimotodani, M. Uchigashima, and M. Watanabe Endocannabinoid-Mediated Control of Synaptic Transmission Physiol Rev, January 1, 2009; 89(1): 309 - 380. [Abstract] [Full Text] [PDF]

				M. Kano, K. Hashimoto, and T. Tabata Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination Phil Trans R Soc B, June 27, 2008; 363(1500): 2173 - 2186. [Abstract] [Full Text] [PDF]

				A. R. Best and W. G. Regehr Serotonin Evokes Endocannabinoid Release and Retrogradely Suppresses Excitatory Synapses J. Neurosci., June 18, 2008; 28(25): 6508 - 6515. [Abstract] [Full Text] [PDF]

				N. Wada, Y. Kishimoto, D. Watanabe, M. Kano, T. Hirano, K. Funabiki, and S. Nakanishi Conditioned eyeblink learning is formed and stored without cerebellar granule cell transmission PNAS, October 16, 2007; 104(42): 16690 - 16695. [Abstract] [Full Text] [PDF]

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				Y. Hashimotodani, T. Ohno-Shosaku, and M. Kano Endocannabinoids and Synaptic Function in the CNS Neuroscientist, April 1, 2007; 13(2): 127 - 137. [Abstract] [PDF]

				Y. Hashimotodani, T. Ohno-Shosaku, and M. Kano Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus J. Neurosci., January 31, 2007; 27(5): 1211 - 1219. [Abstract] [Full Text] [PDF]

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