The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone
The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone
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DOI：
10.1038/nn2052
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发表时间：
2008-03-01
影响因子：
25
通讯作者：
El Mestikawy, Salah
中科院分区：
文献类型：
--
作者：
Gras, Christelle;Amilhon, Benedicte;El Mestikawy, Salah
囊泡转运蛋白的三个亚型积累谷氨酸到突触小泡，以促进其囊泡释放。其中一种亚型VGLUT3在神经元中表达，包括已知释放其他经典递质的胆碱能纹状体间神经元。在这里，我们发现SLc17a8基因(也被称为Vher3)的破坏导致了一种意想不到的低胆碱能纹状体表型。与野生型小鼠相比，Vlut3(-/-)小鼠对可卡因的反应更快，更不容易发生氟哌啶醇诱导的惊厥，缺乏VGLUT3的纹状体脑片中乙酰胆碱的释放减少。这些表型与VGLUT3和囊泡乙酰胆碱转运体(VAChT)在纹状体突触小泡中的共存以及谷氨酸对囊泡乙酰胆碱摄取的协同作用的丧失有关。我们认为，两个递质之间的囊泡协同作用是Vacht生物能量学失衡的结果，Vacht需要阴离子共进入才能继续囊泡填充。我们的研究揭示了谷氨酸对胆碱能突触的一种先前未知的作用，具有潜在的功能和药理学意义。
Three subtypes of vesicular transporters accumulate glutamate into synaptic vesicles to promote its vesicular release. One of the subtypes, VGLUT3, is expressed in neurons, including cholinergic striatal interneurons, that are known to release other classical transmitters. Here we showed that disruption of the Slc17a8 gene (also known as Vglut3) caused an unexpected hypocholinergic striatal phenotype. Vglut3(-/-) mice were more responsive to cocaine and less prone to haloperidol-induced catalepsy than wild-type littermates, and acetylcholine release was decreased in striatum slices lacking VGLUT3. These phenotypes were associated with a colocalization of VGLUT3 and the vesicular acetylcholine transporter (VAChT) in striatal synaptic vesicles and the loss of a synergistic effect of glutamate on vesicular acetylcholine uptake. We propose that this vesicular synergy between two transmitters is the result of the unbalanced bioenergetics of VAChT, which requires anion co-entry for continuing vesicular filling. Our study reveals a previously unknown effect of glutamate on cholinergic synapses with potential functional and pharmacological implications.