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The Journal of Neuroscience, January 17, 2007, 27(3):496-506; doi:10.1523/JNEUROSCI.4644-06.2007

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Cellular/Molecular
Tonic Enhancement of Endocannabinoid-Mediated Retrograde Suppression of Inhibition by Cholinergic Interneuron Activity in the Striatum

Madoka Narushima,^1,2,3 Motokazu Uchigashima,⁴ Masahiro Fukaya,⁴ Minoru Matsui,⁵ Toshiya Manabe,^3,5 Kouichi Hashimoto,^1,3 Masahiko Watanabe,⁴ and Masanobu Kano^1,2

¹Department of Cellular Neuroscience, Osaka University, Graduate School of Medicine, Yamada-oka, Suita 565-0871, Japan, ²Department of Cellular Neurophysiology, Graduate School of Medical Science, Kanazawa University, Takara-machi, Kanazawa 920-8640, Japan, ³Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 102-8666, Japan, ⁴Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan, and ⁵Division of Neuronal Network, Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

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

Tonically active cholinergic interneurons in the striatum modulate activities of striatal outputs from medium spiny (MS) neurons and significantly influence overall functions of the basal ganglia. Cellular mechanisms of this modulation are not fully understood. Here we show that ambient acetylcholine (ACh) derived from tonically active cholinergic interneurons constitutively upregulates depolarization-induced release of endocannabinoids from MS neurons. The released endocannabinoids cause transient suppression of inhibitory synaptic inputs to MS neurons through acting retrogradely onto presynaptic CB₁ cannabinoid receptors. The effects were mediated by postsynaptic M₁ subtype of muscarinic ACh receptors, because the action of a muscarinic agonist to release endocannabinoids and the enhancement of depolarization-induced endocannabinoid release by ambient ACh were both deficient in M₁ knock-out mice and were blocked by postsynaptic infusion of guanosine-5'-O-(2-thiodiphosphate). Suppression of spontaneous firings of cholinergic interneurons by inhibiting I_h current reduced the depolarization-induced release of endocannabinoids. Conversely, elevation of ambient ACh concentration by inhibiting choline esterase significantly enhanced the endocannabinoid release. Paired recording from a cholinergic interneuron and an MS neuron revealed that the activity of single cholinergic neuron could influence endocannabinoid-mediated signaling in neighboring MS neurons. These results clearly indicate that striatal endocannabinoid-mediated modulation is under the control of cholinergic interneuron activity. By immunofluorescent and immunoelectron microscopic examinations, we demonstrated that M₁ receptor was densely distributed in perikarya and dendrites of dopamine D₁ or D₂ receptor-positive MS neurons. Thus, we have disclosed a novel mechanism by which the muscarinic system regulates striatal output and may contribute to motor control.

Key words: CB₁ receptor; acetylcholine; muscarinic receptor; DSI; medium spiny neuron; basal ganglia

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Received Oct. 26, 2006; revised Nov. 28, 2006; accepted Nov. 29, 2006.

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

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