MOLECULAR ANALYSIS OF THE DROSOPHILA GABA TRANSPORTERS

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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.