title: Netrin-1 promotes excitatory synaptogenesis between cortical neurons by initiating synapse assembly.
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.
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, and McGill Program in NeuroEngineering, McGill University, Montreal, Quebec, Canada, H3A 2B4, Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Centre, Montreal General Hospital, Montreal, Quebec, Canada, H3G 1A4, and Department of Physics, McGill University, Montreal, Quebec, Canada, H3A 2T8.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Goldman
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Ashour
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Magdesian
authors.forename: Nicolas X
authors.initials: NX
authors.lastname: Tritsch
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Harris
authors.forename: Nicolas
authors.initials: N
authors.lastname: Christofi
authors.forename: Raja
authors.initials: R
authors.lastname: Chemali
authors.forename: Yaakov E
authors.initials: YE
authors.lastname: Stern
authors.forename: Greta
authors.initials: G
authors.lastname: Thompson-Steckel
authors.forename: Pavel
authors.initials: P
authors.lastname: Gris
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Glasgow
authors.forename: Peter
authors.initials: P
authors.lastname: Grutter
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Bouchard
authors.forename: Edward S
authors.initials: ES
authors.lastname: Ruthazer
authors.forename: David
authors.initials: D
authors.lastname: Stellwagen
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology / Q000378:metabolism / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000502:physiology*; D000075388:Netrin-1; D055495:Neurogenesis / Q000235:genetics; D017966:Pyramidal Cells / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism* / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1