Article: article from journal or magazin.
PSD-95 promotes synaptogenesis and multiinnervated spine formation through nitric oxide signaling
Journal of Cell Biology
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.
Animals Cyclic GMP/analogs & derivatives/pharmacology Dendritic Spines/drug effects/enzymology/*metabolism/ultrastructure Intracellular Signaling Peptides and Proteins/*metabolism Membrane Proteins/*metabolism Mice NIH 3T3 Cells Nitric Oxide/*metabolism Nitric Oxide Synthase Type I/metabolism Nitroso Compounds/pharmacology *Organogenesis/drug effects Protein Binding/drug effects Pyramidal Cells/drug effects/enzymology/ultrastructure Rats *Signal Transduction/drug effects Synapses/drug effects/enzymology/*metabolism/ultrastructure Transfection
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