Molecular and Morphological Configuration for 2-Arachidonoylglycerol-Mediated Retrograde Signaling at Mossy Cell-Granule Cell Synapses in the Dentate Gyrus
Molecular and Morphological Configuration for 2-Arachidonoylglycerol-Mediated Retrograde Signaling at Mossy Cell-Granule Cell Synapses in the Dentate Gyrus
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DOI：
10.1523/jneurosci.5665-10.2011
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发表时间：
2011-05-25
影响因子：
5.3
通讯作者：
Watanabe, Masahiko
中科院分区：
文献类型：
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作者：
Uchigashima, Motokazu;Yamazaki, Maya;Watanabe, Masahiko
2-花生四烯酸甘油（2-AG）是内源性大麻素，介导脑中神经传递的逆行抑制。在本研究中，我们研究了2-AG信号系统在苔藓细胞（MC）-颗粒细胞（GC）突触在小鼠齿状回，兴奋性循环回路，内源性大麻素被认为是抑制癫痫发生。首先，我们通过电生理学表明，由二酰甘油脂肪酶α（DGL α）产生的2-AG介导了去极化诱导的兴奋抑制及其在MC-GC突触处由I组代谢型谷氨酸受体激活引起的增强，因为它们在DGL α基因敲除小鼠中被消除。免疫组织化学显示，DGL α在GC棘的颈部富集，与MC终末形成突触，而大麻素CB（1）受体在MC轴突的终末部分聚集。另一方面，主要的2-AG降解酶，单酰基甘油脂肪酶（MGL），是不存在的MC-GC突触，但在星形胶质细胞和一些抑制性终端的表达。连续电子显微镜证实，给定的GC棘由单个MC末端支配，并且还与其他MC末端非突触接触，与邻近的其他GC棘形成突触。MGL表达元件，但是，差覆盖GC棘，占17%的总表面的GC棘的星形胶质细胞和4%的抑制性终端。我们的研究结果为2-AG介导的MC-GC突触传递的逆行抑制提供了基础，并且还表明从激活的GC棘释放的2-AG通过逃避酶降解而容易接近附近的MC-GC突触。这种分子解剖结构将有助于在增强兴奋后调节齿状回中的网络活动。
2-Arachidonoylglycerol (2-AG) is the endocannabinoid that mediates retrograde suppression of neurotransmission in the brain. In the present study, we investigated the 2-AG signaling system at mossy cell (MC)-granule cell (GC) synapses in the mouse dentate gyrus, an excitatory recurrent circuit where endocannabinoids are thought to suppress epileptogenesis. First, we showed by electrophysiology that 2-AG produced by diacylglycerol lipase alpha (DGL alpha) mediated both depolarization-induced suppression of excitation and its enhancement by group I metabotropic glutamate receptor activation at MC-GC synapses, as they were abolished in DGL alpha-knock-out mice. Immunohistochemistry revealed that DGL alpha was enriched in the neck portion of GC spines forming synapses with MC terminals, whereas cannabinoid CB(1) receptors accumulated in the terminal portion of MC axons. On the other hand, the major 2-AG-degrading enzyme, monoacylglycerol lipase (MGL), was absent at MC-GC synapses but was expressed in astrocytes and some inhibitory terminals. Serial electron microscopy clarified that a given GC spine was innervated by a single MC terminal and also contacted nonsynaptically by other MC terminals making synapses with other GC spines in the neighborhood. MGL-expressing elements, however, poorly covered GC spines, amounting to 17% of the total surface of GC spines by astrocytes and 4% by inhibitory terminals. Our findings provide a basis for 2-AG-mediated retrograde suppression of MC-GC synaptic transmission and also suggest that 2-AG released from activated GC spines is readily accessible to nearby MC-GC synapses by escaping from enzymatic degradation. This molecular-anatomical configuration will contribute to adjust network activity in the dentate gyrus after enhanced excitation.