Mátyás F, Yanovsky Y, Mackie K, Kelsch W, Misgeld U, Freund T F
Institute of Experimental Medicine, Hungarian Academy of Sciences, PO Box 67, Budapest H-1450, Hungary.
Neuroscience. 2006;137(1):337-61. doi: 10.1016/j.neuroscience.2005.09.005. Epub 2005 Nov 10.
Endocannabinoids, acting via type 1 cannabinoid receptors (CB1), are known to be involved in short-term synaptic plasticity via retrograde signaling. Strong depolarization of the postsynaptic neurons is followed by the endocannabinoid-mediated activation of presynaptic CB1 receptors, which suppresses GABA and/or glutamate release. This phenomenon is termed depolarization-induced suppression of inhibition (DSI) or excitation (DSE), respectively. Although both phenomena have been reported to be present in the basal ganglia, the anatomical substrate for these actions has not been clearly identified. Here we investigate the high-resolution subcellular localization of CB1 receptors in the nucleus accumbens, striatum, globus pallidus and substantia nigra, as well as in the internal capsule, where the striato-nigral and pallido-nigral pathways are located. In all examined nuclei of the basal ganglia, we found that CB1 receptors were located on the membrane of axon terminals and preterminal axons. Electron microscopic examination revealed that the majority of these axon terminals were GABAergic, giving rise to mostly symmetrical synapses. Interestingly, preterminal axons showed far more intense staining for CB1, especially in the globus pallidus and substantia nigra, whereas their terminals were only faintly stained. Non-varicose, thin unmyelinated fibers in the internal capsule also showed strong CB1-labeling, and were embedded in bundles of myelinated CB1-negative axons. The majority of CB1 receptors labeled by immunogold particles were located in the axonal plasma membrane (92.3%), apparently capable of signaling cannabinoid actions. CB1 receptors in this location cannot directly modulate transmitter release, because the release sites are several hundred micrometers away. Interestingly, both the CB1 agonist, WIN55,212-2, as well as its antagonist, AM251, were able to block action potential generation, but via a CB1 independent mechanism, since the effects remained intact in CB1 knockout animals. Thus, our electrophysiological data suggest that these receptors are unable to influence action potential propagation, thus they may not be functional at these sites, but are likely being transported to the terminal fields. The present data are consistent with a role of endocannabinoids in the control of GABA, but not glutamate, release in the basal ganglia via presynaptic CB1 receptors, but also call the attention to possible non-CB1-mediated effects of widely used cannabinoid ligands on action potential generation.
内源性大麻素通过1型大麻素受体（CB1）发挥作用，已知其通过逆行信号传导参与短期突触可塑性。突触后神经元的强烈去极化之后是内源性大麻素介导的突触前CB1受体激活，这会抑制GABA和/或谷氨酸的释放。这种现象分别称为去极化诱导的抑制（DSI）或兴奋（DSE）。尽管据报道这两种现象都存在于基底神经节中，但这些作用的解剖学底物尚未明确确定。在这里，我们研究了伏隔核、纹状体、苍白球和黑质以及内囊中CB1受体的高分辨率亚细胞定位，纹状体-黑质和苍白球-黑质通路位于内囊中。在基底神经节的所有检查核中，我们发现CB1受体位于轴突终末和终末前轴突的膜上。电子显微镜检查显示，这些轴突终末中的大多数是GABA能的，产生的大多是对称突触。有趣的是，终末前轴突对CB1的染色要强得多，尤其是在苍白球和黑质中，而它们的终末染色很淡。内囊中的无曲张、细的无髓纤维也显示出强烈的CB1标记，并嵌入有髓CB1阴性轴突束中。免疫金颗粒标记的大多数CB1受体位于轴突质膜中（92.3%），显然能够传递大麻素作用信号。这个位置的CB1受体不能直接调节递质释放，因为释放位点在几百微米之外。有趣的是，CB1激动剂WIN55,212-2及其拮抗剂AM251都能够阻断动作电位的产生，但通过一种不依赖CB1的机制，因为在CB1基因敲除动物中这些效应仍然存在。因此，我们的电生理数据表明这些受体无法影响动作电位的传播，因此它们在这些位点可能没有功能，但可能正在被转运到终末区域。目前的数据与内源性大麻素通过突触前CB1受体控制基底神经节中GABA而非谷氨酸释放的作用一致，但也提醒人们注意广泛使用的大麻素配体对动作电位产生可能的非CB1介导的效应。
