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The Journal of Neuroscience, July 20, 2005, 25(29):6826-6835; doi:10.1523/JNEUROSCI.0945-05.2005

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Cellular/Molecular
Synaptically Driven Endocannabinoid Release Requires Ca²+-Assisted Metabotropic Glutamate Receptor Subtype 1 to Phospholipase C 4 Signaling Cascade in the Cerebellum

Takashi Maejima,^1,2 Saori Oka,³ Yuki Hashimotodani,¹ Takako Ohno-Shosaku,¹ Atsu Aiba,⁴ Dianqing Wu,⁵ Keizo Waku,³ Takayuki Sugiura,³ and Masanobu Kano¹

¹Department of Cellular Neurophysiology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8640, Japan, ²Department of Developmental Physiology, National Institute for Physiological Science, Okazaki 444-8585, Japan, ³Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan, ⁴Division of Cell Biology, Department of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, and ⁵Department of Genetics and Developmental Biology, University of Connecticut Health Center, Armington, Connecticut 06030

Endocannabinoids mediate retrograde signaling and modulate synaptic transmission in various regions of the CNS. Depolarization-induced elevation of intracellular Ca²⁺ concentration causes endocannabinoid-mediated suppression of excitatory/inhibitory synaptic transmission. Activation of G_q/11-coupled receptors including group I metabotropic glutamate receptors (mGluRs) also causes endocannabinoid-mediated suppression of synaptic transmission. However, precise mechanisms of endocannabinoid production initiated by physiologically relevant synaptic activity remain to be determined. To address this problem, we made whole-cell recordings from Purkinje cells (PCs) in mouse cerebellar slices and examined their excitatory synapses arising from climbing fibers (CFs) and parallel fibers (PFs). We first characterized three distinct modes to induce endocannabinoid release by analyzing CF to PC synapses. The first mode is strong activation of mGluR subtype 1 (mGluR1)-phospholipase C (PLC) 4 cascade without detectable Ca²⁺ elevation. The second mode is Ca²⁺ elevation to a micromolar range without activation of the mGluR1-PLC4 cascade. The third mode is the Ca²⁺-assisted mGluR1-PLC4 cascade that requires weak mGluR1 activation and Ca²⁺ elevation to a submicromolar range. By analyzing PF to PC synapses, we show that the third mode is essential for effective endocannabinoid release from PCs by excitatory synaptic activity. Furthermore, our biochemical analysis demonstrates that combined weak mGluR1 activation and mild depolarization in PCs effectively produces 2-arachidonoylglycerol (2-AG), a candidate of endocannabinoid, whereas either stimulus alone did not produce detectable 2-AG. Our results strongly suggest that under physiological conditions, excitatory synaptic inputs to PCs activate the Ca²⁺-assisted mGluR1-PLC4 cascade, and thereby produce 2-AG, which retrogradely modulates synaptic transmission to PCs.

Key words: retrograde signaling; 2-arachidonoylglycerol; metabotropic glutamate receptor type 1; phospholipase C4; calcium; Purkinje cell

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Received March 10, 2005; revised June 7, 2005; accepted June 7, 2005.

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