Perineuronal Net Protein Neurocan Inhibits NCAM/EphA3 Repellent Signaling in GABAergic Interneurons
Open accessAbstract
Perineuronal nets (PNNs) are implicated in closure of critical periods of synaptic plasticity in the brain, but the molecular mechanisms by which PNNs regulate synapse development are obscure. A receptor complex of NCAM and EphA3 mediates postnatal remodeling of inhibitory perisomatic synapses of GABAergic interneurons onto pyramidal cells in the mouse frontal cortex necessary for excitatory/inhibitory balance. Here it is shown that enzymatic removal of PNN glycosaminoglycan chains decreased the density of GABAergic perisomatic synapses in mouse organotypic cortical slice cultures. Neurocan, a key component of PNNs, was expressed in postnatal frontal cortex in apposition to perisomatic synapses of parvalbumin-positive interneurons. Polysialylated NCAM (PSA-NCAM), which is required for ephrin-dependent synapse remodeling, bound less efficiently to neurocan than mature, non-PSA-NCAM. Neurocan bound the non-polysialylated form of NCAM at the EphA3 binding site within the immunoglobulin-2 domain. Neurocan inhibited NCAM/EphA3 association, membrane clustering of NCAM/EphA3 in cortical interneuron axons, EphA3 kinase activation, and ephrin-A5-induced growth cone collapse. These studies delineate a novel mechanism wherein neurocan inhibits NCAM/EphA3 signaling and axonal repulsion, which may terminate postnatal remodeling of interneuron axons to stabilize perisomatic synapses in vivo.
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In the frontal cortex, the number of inhibitory connections to pyramidal cells is decreased after ChABC digestion.
“and in the frontal cortex, the number of inhibitory connections to pyramidal cells is decreased [49].”
From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [49]
Neurocan influences the binding of neural cell adhesion molecule (NCAM) and ephrin type-A receptor 3 (EPHA3) at perisomatic synapses.
“Neurocan is known to influence the binding of neural cell adhesion molecule (NCAM) and ephrin type-A receptor 3 (EPHA3) at perisomatic synapses72.”
From Elimination of the four extracellular matrix molecules tenascin-C, tenascin-R, brevican and neurocan alters the ratio of excitatory and inhibitory synapses (2019) · cites this paper as [72]
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- Authors
- Sullivan, C. S., Gotthard, I., Wyatt, E. V., Bongu, S., Mohan, V., Weinberg, R. J., & Maness, P. F.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Maness, Patricia F.
- Venue
- Scientific Reports
- Published
- 2018-04-18
- Volume
- 8
- Issue
- 1
- Pages
- 6143-6143
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5906663
- OpenAlex
- W2801644687
- Cited by
- 37
- References
- 57
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 6 · 2022: 3 · 2021: 7 · 2020: 10 · 2019: 4 · 2018: 2
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institute of Mental Health (F32MH111189, R01MH101605)
- National Institute of Neurological Disorders and Stroke (R01NS039444, T32NS007431)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Keywords
- perineuronal nets, neurocan, CD56, EphA3, ephrin-A5, polysialylated NCAM, GABAergic interneurons, parvalbumin, excitation-inhibition balance, critical period, synaptic plasticity, axon guidance, frontal cortex, organotypic slice cultures
- MeSH terms
- Animals, Cerebral Cortex, Humans, Interneurons, Protein Binding, Signal Transduction, Neural Cell Adhesion Molecules, Receptor Protein-Tyrosine Kinases, Receptor, EphA3, Mice, Protein Interaction Domains and Motifs, Neurocan, GABAergic Neurons
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