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TitleNetrin-1 promotes excitatory synaptogenesis between cortical neurons by initiating synapse assembly.
Publication TypeJournal Article
Year of Publication2013
AuthorsGoldman, Jennifer S., Mohammed A. Ashour, Margaret H. Magdesian, Nicolas X. Tritsch, Stephanie N. Harris, Nicolas Christofi, Raja Chemali, Yaakov E. Stern, Greta Thompson-Steckel, Pavel Gris, Stephen D. Glasgow, Peter Grutter, Jean-Francois Bouchard, Edward S. Ruthazer, David Stellwagen, and Timothy E. Kennedy
JournalJ Neurosci
Volume33
Issue44
Pagination17278-89
Date Published2013 Oct 30
ISSN1529-2401
KeywordsAnimals, Cells, Cultured, Cerebral Cortex, Excitatory Postsynaptic Potentials, Female, Male, Mice, Mice, Transgenic, Nerve Growth Factors, Neurogenesis, Pyramidal Cells, Rats, Rats, Sprague-Dawley, Synapses, Tumor Suppressor Proteins
Abstract

Netrin-1 is a secreted protein that directs long-range axon guidance during early stages of neural circuit formation and continues to be expressed in the mammalian forebrain during the postnatal period of peak synapse formation. Here we demonstrate a synaptogenic function of netrin-1 in rat and mouse cortical neurons and investigate the underlying mechanism. We report that netrin-1 and its receptor DCC are widely expressed by neurons in the developing mammalian cortex during synapse formation and are enriched at synapses in vivo. We detect DCC protein distributed along the axons and dendrites of cultured cortical neurons and provide evidence that newly translated netrin-1 is selectively transported to dendrites. Using gain and loss of function manipulations, we demonstrate that netrin-1 increases the number and strength of excitatory synapses made between developing cortical neurons. We show that netrin-1 increases the complexity of axon and dendrite arbors, thereby increasing the probability of contact. At sites of contact, netrin-1 promotes adhesion, while locally enriching and reorganizing the underlying actin cytoskeleton through Src family kinase signaling and m-Tor-dependent protein translation to locally cluster presynaptic and postsynaptic proteins. Finally, we demonstrate using whole-cell patch-clamp electrophysiology that netrin-1 increases the frequency and amplitude of mEPSCs recorded from cortical pyramidal neurons. These findings identify netrin-1 as a synapse-enriched protein that promotes synaptogenesis between mammalian cortical neurons.

DOI10.1523/JNEUROSCI.1085-13.2013
Alternate JournalJ. Neurosci.
PubMed ID24174661
Grant List / / Canadian Institutes of Health Research / Canada