title: DCC expression by neurons regulates synaptic plasticity in the adult brain.
abstract: The transmembrane protein deleted in colorectal cancer (DCC) and its ligand, netrin-1, regulate synaptogenesis during development, but their function in the mature central nervous system is unknown. Given that DCC promotes cell-cell adhesion, is expressed by neurons, and activates proteins that signal at synapses, we hypothesized that DCC expression by neurons regulates synaptic function and plasticity in the adult brain. We report that DCC is enriched in dendritic spines of pyramidal neurons in wild-type mice, and we demonstrate that selective deletion of DCC from neurons in the adult forebrain results in the loss of long-term potentiation (LTP), intact long-term depression, shorter dendritic spines, and impaired spatial and recognition memory. LTP induction requires Src activation of NMDA receptor (NMDAR) function. DCC deletion severely reduced Src activation. We demonstrate that enhancing NMDAR function or activating Src rescues LTP in the absence of DCC. We conclude that DCC activation of Src is required for NMDAR-dependent LTP and certain forms of learning and memory.
authors.affiliation: Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Horn
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Glasgow
authors.forename: Delphine
authors.initials: D
authors.lastname: Gobert
authors.forename: Sarah-Jane
authors.initials: SJ
authors.lastname: Bull
authors.forename: Tamarah
authors.initials: T
authors.lastname: Luk
authors.forename: Jacklyn
authors.initials: J
authors.lastname: Girgis
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Tremblay
authors.forename: Danielle
authors.initials: D
authors.lastname: McEachern
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bouchard
authors.forename: Michael
authors.initials: M
authors.lastname: Haber
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
authors.forename: Paul
authors.initials: P
authors.lastname: Krimpenfort
authors.forename: Keith K
authors.initials: KK
authors.lastname: Murai
authors.forename: Anton
authors.initials: A
authors.lastname: Berns
authors.forename: Guy
authors.initials: G
authors.lastname: Doucet
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Chapman
authors.forename: Edward S
authors.initials: ES
authors.lastname: Ruthazer
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D000075389:DCC Receptor; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D004789:Enzyme Activation; D017353:Gene Deletion; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017774:Long-Term Potentiation; D018782:Maze Learning; D008568:Memory; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism; D000075388:Netrin-1; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000075389:DCC Receptor; C501910:Dcc protein, mouse; C501912:Dcc protein, rat; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D019061:src-Family Kinases; D051966:Phospholipase C gamma