PSD-95 promotes synaptogenesis and multiinnervated spine formation through nitric oxide signaling |
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| Authors: | Irina Nikonenko Bernadett Boda Sylvain Steen Graham Knott Egbert Welker Dominique Muller |
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| Affiliation: | 1.Department of Fundamental Neuroscience, Geneva Neuroscience Center, University of Geneva School of Medicine, CH-1211 Geneva, Switzerland;2.Département de Biologie Cellulaire et de Morphologie, Université de Lausanne, CH-1005 Lausanne, Switzerland;3.Interdisciplinary Center for Electron Microscopy, Swiss Federal Institute of Technology, CH-1015 Lausanne, Switzerland |
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| 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 PDZ2 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. |
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