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PSD-95 promotes synaptogenesis and multiinnervated spine formation through nitric oxide signaling

Knott, Graham
Welker, Egbert
Published in The Journal of Cell Biology. 2008, vol. 183, no. 6, p. 1115-1127
Abstract Postsynaptic density 95 (PSD-95) is an important regulator of synaptic structure and plasticity. However, its contribution to synapse formation and organization remains unclear. Using a combined electron microscopic, genetic, and pharmacological approach, we uncover a new mechanism through which PSD-95 regulates synaptogenesis. We find that PSD-95 overexpression affected spine morphology but also promoted the formation of multiinnervated spines (MISs) contacted by up to seven presynaptic terminals. The formation of multiple contacts was specifically prevented by deletion of the PDZ(2) domain of PSD-95, which interacts with nitric oxide (NO) synthase (NOS). Similarly, PSD-95 overexpression combined with small interfering RNA-mediated down-regulation or the pharmacological blockade of NOS prevented axon differentiation into varicosities and multisynapse formation. Conversely, treatment of hippocampal slices with an NO donor or cyclic guanosine monophosphate analogue induced MISs. NOS blockade also reduced spine and synapse density in developing hippocampal cultures. These results indicate that the postsynaptic site, through an NOS-PSD-95 interaction and NO signaling, promotes synapse formation with nearby axons.
Keywords AnimalsCyclic GMP/analogs & derivatives/pharmacologyDendritic Spines/drug effects/enzymology/metabolism/ultrastructureIntracellular Signaling Peptides and Proteins/metabolismMembrane Proteins/metabolismMiceNIH 3T3 CellsNitric Oxide/metabolismNitric Oxide Synthase Type I/metabolismNitroso Compounds/pharmacologyOrganogenesis/drug effectsProtein Binding/drug effectsPyramidal Cells/drug effects/enzymology/ultrastructureRatsSignal Transduction/drug effectsSynapses/drug effects/enzymology/metabolism/ultrastructureTransfection
Stable URL https://archive-ouverte.unige.ch/unige:1295
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Other version: http://jcb.rupress.org/cgi/content/full/183/6/1115
PMID: 19075115
Research group Plasticité des synapses excitatrices (76)

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Deposited on : 2009-04-01

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