MOLECULAR ANALYSIS OF THE DROSOPHILA GABA TRANSPORTERS

描述：（申请人摘要） 发射器再摄取机制不仅对于终止 神经递质信号在突触间隙，但为了维持 突触前神经元内的递质储存。GABA的再摄取， 脊椎动物和无脊椎动物神经抑制性神经递质 系统，是终止信号传播的主要机制 GABA释放GABA能神经传递的扰动被认为是 是痴呆症、精神分裂症和癫痫的病因之一。的目标 这项工作是从分子水平上表征多种GABA转运蛋白， 果蝇（DGATs），并利用这一模式的独特资产 系统研究正常GABA中扰动的功能后果 再吸收机制。实验上可获得的GABA的存在 果蝇中的转运蛋白亚型促进了分子和遗传学方法 有助于了解GABA的作用及其对动物行为的影响。 哺乳动物GABA转运蛋白基因座的多样性被认为是 GABA能神经传递的不同方面;初步工作表明， 果蝇也是如此。因此，靶向GABA再摄取优于 靶向GABA的合成，因为有超过3000个GABA能神经元， 果蝇CNS。本申请提出（1）识别和验证 表征DGAT家族的不同成员，（2）确定其时间 和空间表达，以提供对它们的功能作用的洞察，以及（3） 确定干扰的GABA能神经传递的行为后果， 使用药物干预和过度表达 一种特殊的GABA转运体果蝇的GABA转运蛋白 与它们的哺乳动物对应物同源，因此所提出的实验 将扩展我们对控制神经元的基本调节机制的知识， 兴奋性，并将提供信息，导致改善 痴呆和癫痫的治疗目标。

DESCRIPTION: (Applicant's Abstract) Transmitter reuptake mechanisms are essential not only for terminating neurotransmitter signaling at the synaptic cleft, but for maintaining transmitter stores within the presynaptic neuron. Reuptake of GABA, the major inhibitory neurotransmitter in both vertebrate and invertebrate nervous systems, is the primary mechanism for termination of the signal propagated by GABA release. Perturbations in GABAergic neurotransmission are believed to underlie the etiologies of dementias, schizophrenia, and epilepsy. The goal of this work is to molecularly characterize the multiple GABA transporters in Drosophila melanogaster (DGATs), and to utilize the unique assets of this model system to study the functional consequences of perturbations in normal GABA reuptake mechanisms. The existence of experimentally accessible GABA transporter subtypes in Drosophila facilitates a molecular and genetic approach to the understanding of the actions of GABA and its effects on animal behavior. Diversity in the mammalian GABA transporter locus is believed to serve different aspects of GABAergic neurotransmission; preliminary work suggests the same is true in Drosophila. Targeting GABA reuptake is thus preferable to targeting GABA synthesis, since there are over 3000 GABAergic neurons in the Drosophila CNS. This application proposes to (1) identify and pharmacologically characterize distinct members of the DGAT family, (2) identify their temporal and spatial expression to provide insight into their functional roles, and (3) determine the behavioral consequences of perturbed GABAergic neurotransmission, using both pharmacological intervention and transgenic animals that overexpress a specific GABA transporter. The Drosophila GABA transporters are strikingly homologous to their mammalian counterparts, and thus the proposed experiments will extend our knowledge of basic regulatory mechanisms governing neuronal excitability, and will also provide information resulting in improved therapeutic targets for dementia and epilepsies.