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Control of neural circuit function by the endocannabinoid 2-arachidonoylglycerol

開催日 2014/9/12
時間 15:00 - 17:00
会場 Room F(302)
Chairperson(s) 狩野 方伸 / Masanobu Kano (東京大学大学院医学系研究科 神経生理学分野 / Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Japan)
渡辺 雅彦 / Masahiko Watanabe (北海道大学大学院医学研究科 解剖学講座 解剖発生学分野 / Department of Anatomy, Hokkaido University Graduate School of Medicine, Japan)

The endocannabinoid 2-arachidonoyl glycerol suppresses epileptic seizures through the activation of CB1 and CB2 receptors

  • S2-F-2-5
  • 菅谷 佑樹 / Yuki Sugaya:1 山崎 真弥 / Maya Yamazaki:2 﨑村 建司 / Kenji Sakimura:2 狩野 方伸 / Masanobu Kano:1 
  • 1:東京大院・医・神経生理 / Dept. Neurophysiol., Univ of Tokyo, Tokyo, Japan 2:新潟大・脳研・細胞神経生物 / Dept. Cell. Neurobiol., Brain Res. Inst., Niigata Univ., Niigata, Japan 

Endogenous cannabinoids (endocannabinoids) suppress seizures through cannabinoid CB1 receptors. However, it is still unclear which of the two major endocannabinoids suppresses seizures and whether cannabinoid CB2 receptors are also involved in the protection against seizures. We have recently demonstrated that 2-arachidonoyl glycerol (2-AG) produced by diacylglycerol lipase α (DGLα) is the endocannabinoid that mediates retrograde synaptic suppression. The present study was aimed at elucidating the roles of 2-AG mediated signaling during seizures. We used kainite (30 mg/kg, i.p.) for the induction of seizures. The latency to the onset of generalized tonic clonic seizures (GTCS) was determined in the wild-type and the DGLα knock-out mice. Kainate seizures were also induced in the wild-type mice treated with CB1 antagonist, AM251 (5 mg/kg, i.p.), and/or CB2 antagonist, AM630 (2 mg/kg, i.p.). We found that the latency was significantly shorter in the DGLα knock-out mice compared to that of the wild-type littermates. All of the DGLα knock-out mice died within 30 min after the kainite injection whereas 6 of 7 wild-type littermates survived. The acute blockade of CB1 receptors also resulted in shorter latency compared to the vehicle treatment. Importantly, the acute blockade of CB1 and CB2 receptors significantly shortened the latency compared to that during the blockade of CB1 receptors. The latency of the mice treated with AM251 and AM630 was comparable to that of the DGLα knock-out mice. All of the mice treated with AM251 and AM630 died within 30 min after the kainite injection. We also found that the blockade of 2-AG hydrolysis by JZL184 (4 mg/kg, i.p.) significantly reduced the number of spontaneous seizures during the course of kainate-induced epileptogenesis in wild-type mice. These results suggest that the 2-AG-mediated signaling critically suppresses the abnormal excitability through CB1 and CB2 receptors and might be a possible target for the treatment of epilepsy.

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