PP2A and GSK-3beta act antagonistically to regulate active zone development.
The synapse is composed of an active zone apposed to a postsynaptic cluster of neurotransmitter receptors. Each Drosophila neuromuscular junction comprises hundreds of such individual release sites apposed to clusters of glutamate receptors. Here, we show that protein phosphatase 2A (PP2A) is required for the development of structurally normal active zones opposite glutamate receptors. When PP2A is inhibited presynaptically, many glutamate receptor clusters are unapposed to Bruchpilot (Brp), an active zone protein required for normal transmitter release. These unapposed receptors are not due to presynaptic retraction of synaptic boutons, since other presynaptic components are still apposed to the entire postsynaptic specialization. Instead, these data suggest that Brp localization is regulated at the level of individual release sites. Live imaging of glutamate receptors demonstrates that this disruption to active zone development is accompanied by abnormal postsynaptic development, with decreased formation of glutamate receptor clusters. Remarkably, inhibition of the serine-threonine kinase GSK-3beta completely suppresses the active zone defect, as well as other synaptic morphology phenotypes associated with inhibition of PP2A. These data suggest that PP2A and GSK-3beta function antagonistically to control active zone development, providing a potential mechanism for regulating synaptic efficacy at a single release site.
Viquez
Natasha M
NM
Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Füger
Petra
P
Valakh
Vera
V
Daniels
Richard W
RW
Rasse
Tobias M
TM
DiAntonio
Aaron
A
D000818:Animals; D030801:Animals, Genetically Modified; D003599:Cytoskeleton / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D055032:Electron Microscope Tomography / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018613:Microscopy, Confocal; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D017729:Presynaptic Terminals / Q000378:metabolism / Q000648:ultrastructure; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D017470:Receptors, Glutamate / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
C510146:BRP protein, Drosophila; D029721:Drosophila Proteins; D017470:Receptors, Glutamate; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2