Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum
Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum
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DOI：
10.1523/jneurosci.0448-07.2007
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发表时间：
2007-04-04
影响因子：
5.3
通讯作者：
Watanabe, Masahiko
中科院分区：
文献类型：
--
作者：
Uchigashima, Motokazu;Narushima, Madoka;Watanabe, Masahiko
内源性大麻素（endocannabinoids）介导逆行信号，以短期和长期抑制纹状体中棘（MS）神经元突触的递质释放。在膜去极化和 Gq 偶联受体激活后，由二酰甘油 (DAG) 合成内源性大麻素 2-花生四烯酰甘油 (2-AG)。为了了解纹状体中 2-AG 介导的逆行信号传导，我们确定了 2-AG 合成酶、DAG 脂肪酶-α (DAGL α) 及其上游代谢型谷氨酸受体 5 (mGluR5) 和毒蕈碱乙酰胆碱受体 1 (M-1) 的精确亚细胞分布。 DAGLα、mGluR5和M-1均丰富地分布在MS神经元的体细胞树突表面，但它们的亚细胞分布不同。尽管 mGluR5 和 DAGL α 水平在棘中最高，并在突触周围区域累积，但 M-1 水平在棘中最低，并且被排除在富含 mGluR5 的突触周围区域之外。这些亚细胞排列表明，mGluR5 和 M-1 可能对 MS 神经元中内源性大麻素介导的去极化诱导的抑制抑制 (DSI) 和去极化诱导的兴奋抑制 (DSE) 产生不同的影响。事实上，mGluR5 激活增强了 DSI 和 DSE，而 M-1 激活仅增强了 DSI。重要的是，DSI、DSE 和受体驱动的内源性大麻素介导的抑制均被 DAG 脂肪酶抑制剂四氢利普他汀消除，表明 2-AG 是介导 MS 神经元兴奋性和抑制性突触逆行抑制的主要内源性大麻素。因此，2-AG 的主要靶标 CB1 大麻素受体在 MS 神经元和小清蛋白阳性中间神经元的 GABA 能轴突末端以高水平存在，而在兴奋性皮质纹状体传入神经上以低水平存在。因此，内源性大麻素信号分子被排列为根据分别由 mGluR5 和 M-1 受体测量的皮质活动和胆碱能张力来有效调节 MS 神经元的兴奋性。
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-alpha(DAGL alpha), and its upstream metabotropic glutamate receptor 5 (mGluR5) and muscarinic acetylcholine receptor 1 (M-1). DAGL alpha, mGluR5, and M-1 were all richly distributed on the somatodendritic surface of MS neurons, but their subcellular distributions were different. Although mGluR5 and DAGL alpha levels were highest in spines and accumulated in the perisynaptic region, M-1 level was lowest in spines and was rather excluded from the mGluR5-rich perisynaptic region. These subcellular arrangements suggest that mGluR5 and M-1 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 M-1 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 M-1 receptors, respectively.