title: Postsynaptic regulation of synaptic plasticity by synaptotagmin 4 requires both C2 domains.
abstract: Ca(2+) influx into synaptic compartments during activity is a key mediator of neuronal plasticity. Although the role of presynaptic Ca(2+) in triggering vesicle fusion though the Ca(2+) sensor synaptotagmin 1 (Syt 1) is established, molecular mechanisms that underlie responses to postsynaptic Ca(2+) influx remain unclear. In this study, we demonstrate that fusion-competent Syt 4 vesicles localize postsynaptically at both neuromuscular junctions (NMJs) and central nervous system synapses in Drosophila melanogaster. Syt 4 messenger RNA and protein expression are strongly regulated by neuronal activity, whereas altered levels of postsynaptic Syt 4 modify synaptic growth and presynaptic release properties. Syt 4 is required for known forms of activity-dependent structural plasticity at NMJs. Synaptic proliferation and retrograde signaling mediated by Syt 4 requires functional C2A and C2B Ca(2+)-binding sites, as well as serine 284, an evolutionarily conserved substitution for a key Ca(2+)-binding aspartic acid found in other synaptotagmins. These data suggest that Syt 4 regulates activity-dependent release of postsynaptic retrograde signals that promote synaptic plasticity, similar to the role of Syt 1 as a Ca(2+) sensor for presynaptic vesicle fusion.
authors.affiliation: Department of Biology, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Cynthia F
authors.initials: CF
authors.lastname: Barber
authors.forename: Ramon A
authors.initials: RA
authors.lastname: Jorquera
authors.forename: Jan E
authors.initials: JE
authors.lastname: Melom
authors.forename: J Troy
authors.initials: JT
authors.lastname: Littleton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D050678:Complement C2a / Q000235:genetics / Q000378:metabolism; D050679:Complement C2b / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D009469:Neuromuscular Junction / Q000378:metabolism; D009473:Neuronal Plasticity; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013569:Synapses / Q000378:metabolism*; D050857:Synaptotagmins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D050679:Complement C2b; D050857:Synaptotagmins; D050678:Complement C2a