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Regulation of Transmission at Monoaminergic Neurons: A Synapse-to-Circuit Study in Drosophila

  • Author(s): Chen, Audrey
  • Advisor(s): Krantz, David E
  • Schweizer, Felix E
  • et al.
Abstract

The Drosophila vesicular monoamine transporter (DVMAT) regulates the loading and storage of monoaminergic transmitters in secretory vesicles, and proper localization to vesicles is required for the exocytotic release of neurotransmitters such as dopamine and serotonin. By genetically modifying the availability of vesicular monoamine transporters in specific monoamine neurons, I examine amine requirements for aspects of behavior and interactions between aminergic systems. I demonstrate that some behaviors rely predominantly on octopaminergic circuits with little apparent input from either serotonin or dopamine. In contrast, other behaviors can be rescued by expressing DVMAT in octopaminergic or dopaminergic neurons, suggesting potentially redundant circuits. Rescue of major aspects of adult locomotion and startle behavior required octopamine, but complementary roles were observed for serotonin

and dopamine. Interestingly, adult circadian behavior could not be rescued by expression of DVMAT in a single subtype of aminergic neurons, but required at least two systems, suggesting the possibility of unexpected cooperative interactions. Studies using the temperature-sensitive GAL80 inducible transgene system demonstrate that the temporal demand for DVMAT yields a large degree of flexibility with causes still left unclear. In order to understand the cellular mechanisms which regulate monoamine release, my work also examines motifs involved in trafficking vesicular monomamine transporters to the axon terminal and appropriately on synaptic vesicles during rounds of exo- and endocytosis. The C-terminus of DVMAT encodes a tyrosine-based motif (YXX�) flanked between a di-leucine motif and downstream acidic residues that have been shown to be involved with endocytosis, sorting to synaptic vesicles and maturation of large dense core vesicles in vitro. I employ fast-capture, in vivo real-time imaging of pH-sensitive pHlourins to track wild-type and mutant DVMAT in intact circuits. My findings suggest that the C-terminus contains trafficking motifs that slow endocytosis kinetics and dampen the presynaptic neuron's ability to recruit vesicles to the plasma membrane. Moreover, the previously described Delta3 deletion disrupts VMAT trafficking to the axon terminal. Combined with results showing that behaviors are differentially sensitive to mutations, these data are among the first to demonstrate that mislocalization of a synaptic protein may preferentially affect specific neuronal circuits and argue that behaviors require varying stringency levels for regulated neurotransmitter release.

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