The Influence of Neurotransmitter Transport on Aminergic Neuromodulation

 描述（由申请方提供）：囊泡单胺转运蛋白（VMAT）是所有胺能神经递质储存和胞吐释放所必需的。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尚不清楚。我们正在使用模式生物果蝇来解决这些问题。到目前为止，我们已经产生的突变减少了果蝇VMAT（DVMAT）的定位到突触囊泡（SV），并增加了其定位到大致密核心囊泡（LDCV）。这些突变的行为后遗症提供了一些关于SV与LDCV的胺释放功能的第一信息。我们现在将产生额外的突变以减少DVMAT对LDCV的定位。这些突变体将有助于进一步的行为测试，也有助于确定神经元中的基本贩运机制。额外的实验将使用这些突变体来定义在胺能与非胺能神经元的贩运之间的差异知之甚少，并确定胺释放的变化如何影响前和后突触功能胺能电路。进一步的行为实验将探索胺释放改变对更复杂行为的影响以及对胺能药物的反应。这些实验的结果将是有意义的，因为他们检查相关的保守的神经调节过程和胺能药物的临床效果的过程。他们是创新的，因为他们利用了几种新的检测方法，因为没有其他实验室已经检查了囊泡转运蛋白的错误运输的体内影响，或者改变神经递质从特定囊泡类型释放的方式的行为影响。

 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.