DCC Expression by Neurons Regulates Synaptic Plasticity in the Adult Brain

SummaryThe 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.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► DCC and netrin-1 are enriched at synapses in the adult mouse forebrain
► DCC is enriched in the PSD and regulates dendritic spine morphology
► LTP induction and memory formation require DCC expression by neurons
► DCC activation of Src is required for NMDAR-dependent LTP in adult CNS