DCC expression by neurons regulates synaptic plasticity in the adult brain

Cell Rep. 2013 Jan 31;3(1):173-85. doi: 10.1016/j.celrep.2012.12.005. Epub 2013 Jan 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Animals
  • Brain / growth & development*
  • Brain / metabolism*
  • DCC Receptor
  • Dendritic Spines / metabolism
  • Dendritic Spines / ultrastructure
  • Enzyme Activation
  • Gene Deletion
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Long-Term Potentiation
  • Maze Learning
  • Memory
  • Mice
  • Nerve Growth Factors / metabolism
  • Netrin-1
  • Neuronal Plasticity*
  • Neurons / metabolism*
  • Neurons / pathology
  • Neurons / ultrastructure
  • Phospholipase C gamma / metabolism
  • Phosphorylation
  • Prosencephalon / metabolism
  • Prosencephalon / pathology
  • Prosencephalon / physiopathology
  • Rats
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Subcellular Fractions / metabolism
  • Synapses / metabolism*
  • Synapses / pathology
  • Synapses / ultrastructure
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / metabolism*
  • src-Family Kinases / metabolism

Substances

  • DCC Receptor
  • Dcc protein, mouse
  • Dcc protein, rat
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • Ntn1 protein, rat
  • Receptors, Cell Surface
  • Receptors, N-Methyl-D-Aspartate
  • Tumor Suppressor Proteins
  • Netrin-1
  • src-Family Kinases
  • Phospholipase C gamma