DCC expression by neurons regulates synaptic plasticity in the adult brain
Open accessAbstract
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.
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Plcg2 in granule cells may be relevant for synaptic transmission and plasticity via induction of hippocampal long-term potentiation (LTP).
“By analogy with Plcg1 function in neurons, Plcg2 in granule cells may be relevant for synaptic transmission and plasticity via induction of hippocampal long-term potentiation LTP [10, 44].”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [44]
The section “DCC Regulates Src, Phospholipase C γ, and Phosphorylated Src Family Kinase Expression” (p. 7) reports reduced PLCγ1 activation in DCC-deficient hippocampi, and “Src Is Essential for LTP Induction” (p. 10) links PLC signaling to LTP. These passages support the Plcg1 analogy, but the paper does not establish a role for Plcg2 in granule cells or show that it induces LTP. (LLM, conf=0.83)
Experimental — accuracy not yet measuredDCC shows abundant expression in dopaminergic neurons, and DCC-deficient mice show altered dopaminergic system organization, culminating in impaired memory, behavior, and reward responses.
“This gene shows abundant expression in dopaminergic neurons, and behavioral studies of DCC-deficient mice show altered dopaminergic system organization, culminating in impaired memory, behavior, and reward responses (46,47).”
From Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication (2014) · cites this paper as [46]
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The Netrin-1 receptor DCC is a regulator of maladaptive responses to chronic morphine administration
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Adamtsl3 mediates DCC signaling to selectively promote GABAergic synapse function
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Roundabout receptor 2 maintains inhibitory control of the adult midbrain
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Dcc haploinsufficiency regulates dopamine receptor expression across postnatal lifespan
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A-kinase Anchoring Protein 79/150 Recruits Protein Kinase C to Phosphorylate Roundabout Receptors
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DCC/netrin-1 regulates cell death in oligodendrocytes after brain injury
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DCC gene network in the prefrontal cortex is associated with total brain volume in childhood
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Control of Male and Female Fertility by the Netrin Axon Guidance Genes
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The E3 ubiquitin ligase TRIM9 regulates synaptic function and actin dynamics in response to netrin-1
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Sleep need driven oscillation of glutamate synaptic phenotypePreprint
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Adult expression of Semaphorins and Plexins is essential for motor neuron survival
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NCK1 Modulates Neuronal Actin Dynamics and Promotes Dendritic Spine, Synapse, and Memory Formation
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- Authors
- Horn, K. E., Glasgow, S. D., Gobert, D., Bull, S.-J., Luk, T., Girgis, J., Tremblay, M.-E., McEachern, D., Bouchard, J.-F., Haber, M., Hamel, E., Krimpenfort, P., Murai, K. K., Berns, A., Doucet, G., Chapman, C. A., Ruthazer, E. S., & Kennedy, T. E.
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- Concordia University (CA)
- Montreal General Hospital (CA)
- The Netherlands Cancer Institute (NL)
- Université de Montréal (CA)
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 3
- Issue
- 1
- Pages
- 173-185
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2129722759
- Cited by
- 147
- References
- 59
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 16 · 2023: 11 · 2022: 12 · 2021: 6 · 2020: 20 · 2019: 13 · 2018: 12 · 2017: 10 · 2016: 6 · 2015: 6 · 2014: 7 · 2013: 10
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship@McGill (McGill) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship@McGill (McGill) (submittedVersion)
- Funders
- Killam Trusts
- Canadian Institutes of Health Research (247564)
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- DCC, netrin-1, synaptic plasticity, long-term potentiation, long-term depression, dendritic spines, Src kinase, NMDA receptor, memory formation, neuronal adhesion, forebrain, pyramidal neurons, learning and memory
- MeSH terms
- Netrin-1, DCC Receptor, Aging, Animals, Brain, Enzyme Activation, Hippocampus, Memory, Nerve Growth Factors, Neuronal Plasticity, Neurons, Phosphorylation, Receptors, Cell Surface, Subcellular Fractions, Synapses, Receptors, N-Methyl-D-Aspartate, Prosencephalon, Gene Deletion, Long-Term Potentiation, Maze Learning, src-Family Kinases, Tumor Suppressor Proteins, Dendritic Spines, Mice, Rats, Phospholipase C gamma
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