Elimination of the Vesicular Acetylcholine Transporter in the Striatum Reveals Regulation of Behaviour by Cholinergic-Glutamatergic Co-Transmission
Elimination of the Vesicular Acetylcholine Transporter in the Striatum Reveals Regulation of Behaviour by Cholinergic-Glutamatergic Co-Transmission
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DOI：
10.1371/journal.pbio.1001194
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发表时间：
2011-11-01
期刊：
影响因子：
9.8
通讯作者：
Prado, Marco A. M.
中科院分区：
文献类型：
--
作者：
Guzman, Monica S.;De Jaeger, Xavier;Prado, Marco A. M.
纹状体中的胆碱能神经元被认为在运动行为和奖励中起主要的调节作用。这些神经元表达两种囊泡转运蛋白，可以将乙酰胆碱或谷氨酸装载到突触囊泡中。因此，胆碱能神经元可以释放这两种神经递质，这使得很难辨别它们对纹状体功能调节的个体贡献。在这里，我们通过选择性消除纹状体胆碱能神经元的囊泡乙酰胆碱转运体（VAChT），剖析了乙酰胆碱释放在小鼠纹状体依赖行为中的具体作用。对几个行为参数的分析表明，在纹状体相关的任务中，VAChT的消除只会产生轻微的影响，不会影响自发运动、可卡因诱导的多动症或其奖励特性。然而，中棘神经元（MSN）的多巴胺能敏感性和直接多巴胺能激动剂反应的行为输出增强，可能是由于纹状体中多巴胺受体的表达/功能增加。这些观察结果表明，纹状体胆碱能神经元在自发运动活动和可卡因奖赏反应中的先前功能是由谷氨酸介导的，而不是由乙酰胆碱释放介导的。我们的实验证明了一群神经元如何使用两种不同的神经递质来不同地调节给定的电路。这些数据还提高了使用VAChT作为靶点来增强多巴胺能功能和降低高纹状体胆碱能活性的可能性，这是帕金森病患者常见的神经化学改变。
Cholinergic neurons in the striatum are thought to play major regulatory functions in motor behaviour and reward. These neurons express two vesicular transporters that can load either acetylcholine or glutamate into synaptic vesicles. Consequently cholinergic neurons can release both neurotransmitters, making it difficult to discern their individual contributions for the regulation of striatal functions. Here we have dissected the specific roles of acetylcholine release for striatal-dependent behaviour in mice by selective elimination of the vesicular acetylcholine transporter (VAChT) from striatal cholinergic neurons. Analysis of several behavioural parameters indicates that elimination of VAChT had only marginal consequences in striatum-related tasks and did not affect spontaneous locomotion, cocaine-induced hyperactivity, or its reward properties. However, dopaminergic sensitivity of medium spiny neurons (MSN) and the behavioural outputs in response to direct dopaminergic agonists were enhanced, likely due to increased expression/function of dopamine receptors in the striatum. These observations indicate that previous functions attributed to striatal cholinergic neurons in spontaneous locomotor activity and in the rewarding responses to cocaine are mediated by glutamate and not by acetylcholine release. Our experiments demonstrate how one population of neurons can use two distinct neurotransmitters to differentially regulate a given circuitry. The data also raise the possibility of using VAChT as a target to boost dopaminergic function and decrease high striatal cholinergic activity, common neurochemical alterations in individuals affected with Parkinson's disease.