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

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

Correspondence to Dominique Muller: Dominique.Muller{at}medecine.unige.ch

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.

Abbreviations used in this paper: AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; cGMP, cyclic guanosine monophosphate; DETA, diethylenetriamine; DIV, day in vitro; L-NAME, L-N^G-nitroarginine methyl ester; LTP, long-term potentiation; MIS, multiinnervated spine; nNOS, neuronal NOS; NO, nitric oxide; NOS, NO synthase; PSD, postsynaptic density.

© 2008 Nikonenko et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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Multiple axons and actions with PSD-95

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