MOLECULAR ANALYSIS OF THE DROSOPHILA GABA TRANSPORTERS

描述：(申请人摘要) 递质再摄取机制不仅对于终止 突触间隙的神经递质信号，但用于维持 递质储存在突触前神经元中。GABA的再摄取，主要的 脊椎动物和无脊椎动物神经中的抑制性神经递质 系统，是终止由 GABA释放。GABA能神经传递的扰动被认为是 痴呆症、精神分裂症和癫痫的病因。的目标是 这项工作是为了从分子水平上表征脑内多个GABA转运体。 并利用这一模型的独特资产 研究正常GABA中扰动的功能后果的系统 再摄取机制。实验上可获得的GABA的存在 果蝇转运蛋白亚型促进分子和遗传途径 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 果蝇的情况也是如此。因此，靶向GABA再摄取比 以GABA合成为靶点，因为在大脑中有3000多个GABA能神经元 果蝇属CNS.本申请建议(1)从药理上识别 确定DGAT家族的不同成员的特征，(2)确定他们的时间 和空间表达，以深入了解它们的功能角色，以及(3) 确定受扰的GABA能神经传递的行为后果， 使用药物干预和过度表达的转基因动物 一种特定的GABA转运蛋白。果蝇的GABA转运体惊人地 与它们的哺乳动物同源，因此拟议的实验 将扩展我们对神经元的基本调控机制的知识 兴奋性，并将提供信息，从而改善 痴呆症和癫痫的治疗靶点。

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.