Molecular Analysis of Drosophila GABA Transporters

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Gamma-aminobutryic acid (GABA) is the principal inhibitory neurotransmitter in both vertebrate and invertebrate nervous systems. GABA transporters largely mediate termination of GABA-stimulated inhibitory responses by the selective reuptake of GABA from the synaptic cleft. In this physiological context, efficient GABA transport mechanisms ensure the fidelity of neurotransmission. In addition, diversity in the mammalian GABA transporter isoforms is believed to regulate different aspects of GABAergic neurotransmission; preliminary work suggests the same is true for Drosophila. We cloned several partial GABA transporter-homologous cDNAs from a Drosophila head library that displayed extensive sequence homology with mammalian GABA transporters. The existence of experimentally accessible GABA transporters in Drosophila (DGATs) facilitates undertaking a molecular- genetic approach to better understand the neurochemical actions of GABA on behaviors. We hypothesize that alterations in GABA-mediated neurotransmission via perturbations in DGAT function will result in aberrant behaviors. We also hypothesize that different members of the DGAT family regulate different aspects of GABA-mediated behaviors. To verify these hypotheses, we will address three specific aims: 1) We will analyze pharmacologically induced behaviors In the adult fly that result from perturbations in GABA transporter function and GABA- mediated neurotransmission. 2) We will identify distinct members of the Drosophila GABA transporter family (DGATs) and functionally characterize the proteins by expressing them in Insect cells. 3) We will analyze the behavioral phenotypes of mutant strains of flies with abnormal GABA transporter expression. The proposed work will extend our knowledge of basic regulatory mechanisms governing GABA-mediated neurotransmission.