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TitlePre- and post-synaptic roles for DCC in memory consolidation in the adult mouse hippocampus.
Publication TypeJournal Article
Year of Publication2020
AuthorsGlasgow, Stephen D., Edwin W. Wong, Greta Thompson-Steckel, Nathalie Marcal, Philippe Séguéla, Edward S. Ruthazer, and Timothy E. Kennedy
JournalMol Brain
Volume13
Issue1
Pagination56
Date Published2020 04 07
ISSN1756-6606
KeywordsAging, Animals, CA1 Region, Hippocampal, CA3 Region, Hippocampal, DCC Receptor, Dendritic Spines, Gene Deletion, Glutamic Acid, Hippocampus, Memory Consolidation, Mice, Inbred C57BL, Neurons, Pyramidal Cells, Spatial Memory, Synapses
Abstract

The receptor deleted in colorectal cancer (DCC) and its ligand netrin-1 are essential for axon guidance during development and are expressed by neurons in the mature brain. Netrin-1 recruits GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and is critical for long-term potentiation (LTP) at CA3-CA1 hippocampal Schaffer collateral synapses, while conditional DCC deletion from glutamatergic neurons impairs hippocampal-dependent spatial memory and severely disrupts LTP induction. DCC co-fractionates with the detergent-resistant component of postsynaptic density, yet is enriched in axonal growth cones that differentiate into presynaptic terminals during development. Specific presynaptic and postsynaptic contributions of DCC to the function of mature neural circuits have yet to be identified. Employing hippocampal subregion-specific conditional deletion of DCC, we show that DCC loss from CA1 hippocampal pyramidal neurons resulted in deficits in spatial memory, increased resting membrane potential, abnormal dendritic spine morphology, weaker spontaneous excitatory postsynaptic activity, and reduced levels of postsynaptic adaptor and signaling proteins; however, the capacity to induce LTP remained intact. In contrast, deletion of DCC from CA3 neurons did not induce detectable changes in the intrinsic electrophysiological properties of CA1 pyramidal neurons, but impaired performance on the novel object place recognition task as well as compromised excitatory synaptic transmission and LTP at Schaffer collateral synapses. Together, these findings reveal specific pre- and post-synaptic contributions of DCC to hippocampal synaptic plasticity underlying spatial memory.

DOI10.1186/s13041-020-00597-2
Alternate JournalMol Brain
PubMed ID32264905
PubMed Central IDPMC7137442
Grant ListPJT-153098 / / Canadian Institute for Health Research (CIHR) / International
FDN-143238 / / Canadian Institute for Health Research (CIHR) / International
PJT-366649 / / Canadian Institute for Health Research (CIHR) / International
PJT-114965 / / Canadian Institute for Health Research (CIHR) / International