DCC Expression by Neurons Regulates Synaptic Plasticity in the Adult Brain
Katherine E. Horn,
Stephen D. Glasgow,
Delphine Gobert,
Sarah-Jane Bull,
Tamarah Luk,
Jacklyn Girgis,
Marie-Eve Tremblay,
Danielle McEachern,
Jean-François Bouchard,
Michael Haber,
Edith Hamel,
Paul Krimpenfort,
Keith K. Murai,
Anton Berns,
Guy Doucet,
C. Andrew Chapman,
Edward S. Ruthazer,
Timothy E. Kennedy
Affiliations
Katherine E. Horn
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
Stephen D. Glasgow
Center for Studies in Behavioural Neurobiology, Department of Psychology, Concordia University, Montreal, QC, H4B 1R6, Canada
Delphine Gobert
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
Sarah-Jane Bull
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
Tamarah Luk
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
Jacklyn Girgis
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
Marie-Eve Tremblay
Groupe de Recherche sur le Système Nerveux Central, Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, QC, H3C 3J7, Canada
Danielle McEachern
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
Jean-François Bouchard
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
Michael Haber
Centre for Research in Neuroscience, Montreal General Hospital, McGill University, Montreal, QC, H3G 1A4, Canada
Edith Hamel
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
Paul Krimpenfort
Department of Molecular Genetics, Cancer Genomics Centre, Centre for Biomedical Genetics, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands
Keith K. Murai
Centre for Research in Neuroscience, Montreal General Hospital, McGill University, Montreal, QC, H3G 1A4, Canada
Anton Berns
Department of Molecular Genetics, Cancer Genomics Centre, Centre for Biomedical Genetics, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands
Guy Doucet
Groupe de Recherche sur le Système Nerveux Central, Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, QC, H3C 3J7, Canada
C. Andrew Chapman
Center for Studies in Behavioural Neurobiology, Department of Psychology, Concordia University, Montreal, QC, H4B 1R6, Canada
Edward S. Ruthazer
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
Timothy E. Kennedy
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, H3A 2B4, Canada
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.
