The Influence of Neurotransmitter Transport on Aminergic Neuromodulation

 描述(由申请人提供)：囊泡单胺转运体(VMATs)是储存和胞吐释放所有胺能神经递质所必需的。VMATs靶向分泌囊泡的机制尚不清楚，破坏其定位的潜在行为后果也尚不清楚。我们正在使用模式生物黑腹果蝇来解决这些问题。到目前为止，我们产生的突变减少了果蝇VMAT(DVMAT)到突触小泡(SVS)的定位，而增加了它到大致密核心小泡(LDCV)的定位。这些突变的行为后遗症提供了一些关于SVS和LDCV释放胺的功能的第一批信息。我们现在将产生额外的突变，以减少DVMAT对LDCV的本地化。这些突变体将对进一步的行为测试有用，也有助于确定神经元的基本运输机制。其他实验将使用这些突变体来定义胺能神经元和非胺能神经元之间鲜为人知的差异，并确定胺释放的变化如何影响胺能回路中突触前和突触后的功能。进一步的行为学实验将探索在更复杂的行为中改变胺释放的影响以及对胺能药物的反应。这些实验的结果将是重要的，因为他们检查了与保守的神经调节过程相关的过程和胺能药物的临床效果。它们具有创新性，因为它们采用了几种新的分析方法，而且还没有其他实验室研究过囊泡转运蛋白的错误运输对体内的影响，或者改变特定类型囊泡释放神经递质的方式对行为的影响。

 DESCRIPTION (provided by applicant): Vesicular monoamine transporters (VMATs) are required for the storage and exocytotic release of all aminergic neurotransmitters. The mechanisms by which VMATs target to secretory vesicles remain unclear and the potential behavioral consequences of disrupting their localization are unknown. We are using the model organism Drosophila melanogaster to address these questions. The mutations we have generated thus far decrease the localization of Drosophila VMAT (DVMAT) to Synaptic Vesicles (SVs) and increase its localization to Large Dense Core Vesicles (LDCVs). The behavioral sequelae of these mutations provide some of the first information on the function of amine release from SVs versus LDCVs. We will now generate additional mutations to decrease the localization of DVMAT to LDCVs. These mutants will be useful for further behavioral tests and also help to define fundamental trafficking mechanisms in neurons. Additional experiments will use these mutants to define the poorly understood differences between trafficking in aminergic versus non-aminergic neurons and to determine how changes in amine release affect pre- and post-synaptic function in aminergic circuits. Further behavioral experiments will explore the affects of altered amine release in more complex behaviors and the response to aminergic drugs. The results of these experiments will be significant because they examine processes relevant to conserved neuromodulatory processes and the clinical effects of aminergic drugs. They are innovative because they exploit several new assays and because no other lab has examined the in vivo effects of mis-trafficking for a vesicular transporter, or the behavioral effects of changing the way neurotransmitters are released from particular vesicle types.