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The Journal of Neuroscience, September 16, 2009, 29(37):11484-11494; doi:10.1523/JNEUROSCI.5584-08.2009

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Cellular/Molecular
PP2A and GSK-3β Act Antagonistically to Regulate Active Zone Development

Natasha M. Viquez,¹ Petra Füger,³ Vera Valakh,¹ Richard W. Daniels,¹ Tobias M. Rasse,³ and Aaron DiAntonio^1,2

¹Department of Developmental Biology and ²Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, and ³Junior Research Group Synaptic Plasticity and Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen D-72076, Germany

Correspondence should be addressed to Aaron DiAntonio, Department of Developmental Biology, Campus Box 8103, 660 S. Euclid, Washington University School of Medicine, St. Louis, MO 63110. Email: diantonio{at}wustl.edu

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-3β 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-3β function antagonistically to control active zone development, providing a potential mechanism for regulating synaptic efficacy at a single release site.

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Received Nov. 21, 2008; revised July 20, 2009; accepted July 27, 2009.

Correspondence should be addressed to Aaron DiAntonio, Department of Developmental Biology, Campus Box 8103, 660 S. Euclid, Washington University School of Medicine, St. Louis, MO 63110. Email: diantonio{at}wustl.edu

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