title: Fife organizes synaptic vesicles and calcium channels for high-probability neurotransmitter release.
abstract: The strength of synaptic connections varies significantly and is a key determinant of communication within neural circuits. Mechanistic insight into presynaptic factors that establish and modulate neurotransmitter release properties is crucial to understanding synapse strength, circuit function, and neural plasticity. We previously identified Drosophila Piccolo-RIM-related Fife, which regulates neurotransmission and motor behavior through an unknown mechanism. Here, we demonstrate that Fife localizes and interacts with RIM at the active zone cytomatrix to promote neurotransmitter release. Loss of Fife results in the severe disruption of active zone cytomatrix architecture and molecular organization. Through electron tomographic and electrophysiological studies, we find a decrease in the accumulation of release-ready synaptic vesicles and their release probability caused by impaired coupling to Ca2+channels. Finally, we find that Fife is essential for the homeostatic modulation of neurotransmission. We propose that Fife organizes active zones to create synaptic vesicle release sites within nanometer distance of Ca2+channel clusters for reliable and modifiable neurotransmitter release.
authors.affiliation: Cell and Molecular Biology Training Program, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Joseph J
authors.identifier: http://orcid.org/0000-0001-8852-9440
authors.initials: JJ
authors.lastname: Bruckner
authors.affiliation: Laboratory of Cell and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Hong
authors.identifier: http://orcid.org/0000-0002-7625-3528
authors.initials: H
authors.lastname: Zhan
authors.affiliation: Laboratory of Cell and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Scott J
authors.identifier: http://orcid.org/0000-0002-0106-8336
authors.initials: SJ
authors.lastname: Gratz
authors.affiliation: Cell and Molecular Biology Training Program, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Monica
authors.initials: M
authors.lastname: Rao
authors.affiliation: Laboratory of Cell and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Fiona
authors.initials: F
authors.lastname: Ukken
authors.affiliation: Laboratory of Cell and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Gregory
authors.identifier: http://orcid.org/0000-0002-6575-508X
authors.initials: G
authors.lastname: Zilberg
authors.affiliation: Cell and Molecular Biology Training Program, University of Wisconsin-Madison, Madison, WI 53706 oconnorgiles@wisc.edu.|Laboratory of Cell and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706.|Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706.
authors.forename: Kate M
authors.identifier: http://orcid.org/0000-0002-2259-8408
authors.initials: KM
authors.lastname: O'Connor-Giles
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D055032:Electron Microscope Tomography; D005838:Genotype; D008297:Male; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity; D010641:Phenotype; D017729:Presynaptic Terminals / Q000378:metabolism*; D011485:Protein Binding; D055366:Synaptic Potentials; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism*; D020692:rab3 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; C578333:Fife protein, Drosophila; D009419:Nerve Tissue Proteins; C577877:RIM protein, Drosophila; D020692:rab3 GTP-Binding Proteins