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Presynaptic Neuronal Pentraxin Receptor Organizes Excitatory and Inhibitory Synapses
Open accessAbstract
Three neuronal pentraxins are expressed in brain, the membrane-bound “neuronal pentraxin receptor” (NPR) and the secreted proteins NP1 and NARP (i.e., NP2). Neuronal pentraxins bind to AMPARs at excitatory synapses and play important, well-documented roles in the activity-dependent regulation of neural circuits via this binding activity. However, it is unknown whether neuronal pentraxins perform roles in synapses beyond modulating postsynaptic AMPAR-dependent plasticity, and whether they may even act in inhibitory synapses. Here, we show that NPR expressed in non-neuronal cells potently induces formation of both excitatory and inhibitory postsynaptic specializations in cocultured hippocampal neurons. Knockdown of NPR in hippocampal neurons, conversely, dramatically decreased assembly and function of both excitatory and inhibitory postsynaptic specializations. Overexpression of NPR rescued the NPR knockdown phenotype but did not in itself change synapse numbers or properties. However, the NPR knockdown decreased the levels of NARP, whereas NPR overexpression produced a dramatic increase in the levels of NP1 and NARP, suggesting that NPR recruits and stabilizes NP1 and NARP on the presynaptic plasma membrane. Mechanistically, NPR acted in excitatory synapse assembly by binding to the N-terminal domain of AMPARs; antagonists of AMPA and GABA receptors selectively inhibited NPR-induced heterologous excitatory and inhibitory synapse assembly, respectively, but did not affect neurexin-1β-induced synapse assembly as a control. Our data suggest that neuronal pentraxins act as signaling complexes that function as general trans-synaptic organizers of both excitatory and inhibitory synapses by a mechanism that depends, at least in part, on the activity of the neurotransmitter receptors at these synapses. SIGNIFICANCE STATEMENT Neuronal pentraxins comprise three neuronal proteins, neuronal pentraxin receptor (NPR) which is a type-II transmembrane protein on the neuronal surface, and secreted neuronal pentraxin-1 and NARP. The general functions of neuronal pentraxins at synapses have not been explored, except for their basic AMPAR binding properties. Here, we examined the functional role of NPR at synapses because it is the only neuronal pentraxin that is anchored to the neuronal cell-surface membrane. We find that NPR is a potent inducer of both excitatory and inhibitory heterologous synapses, and that knockdown of NPR in cultured neurons decreases the density of both excitatory and inhibitory synapses. Our data suggest that NPR performs a general, previously unrecognized function as a universal organizer of synapses.
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“Neuronal pentraxins have been found to be involved in synapse formation and plasticity [37, 38]”
In the citing paper
“The three NPTXs interact, directly or indirectly, with the N-terminal extracellular domain of AMPAR subunits (GluA1, GluA2, GluA3 and GluA4), via their conserved pentraxin domain (Chang et al. 2010; Cho et al. 2008; Lee et al. 2017; Sia et al. 2007; Suzuki et al. 2020).”
From Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration (2022) · cites this paper as Lee et al. 2017
In the citing paper
“A potential role of NPTXR as universal organizer of both excitatory and inhibitory synapses was observed in in vitro studies (Lee et al. 2017).”
From Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration (2022) · cites this paper as Lee et al. 2017
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Metadata
- Authors
- Lee, S.-J., Wei, M., Zhang, C., Maxeiner, S., Pak, C., Calado Botelho, S., Trotter, J., Sterky, F. H., & Südhof, T. C.
- Affiliations
- Stanford Medicine (US)
- Peking University (CN)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-12-16
- Volume
- 37
- Issue
- 5
- Pages
- 1062-1080
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5296791
- OpenAlex
- W2562584466
- Cited by
- 146
- References
- 36
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 28 · 2023: 13 · 2022: 18 · 2021: 21 · 2020: 21 · 2019: 6 · 2018: 9 · 2017: 9
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH052804, R37MH052804)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD078051)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- NARP, excitatory synapses, inhibitory synapses, AMPA receptors, GABA receptors, trans-synaptic signaling, postsynaptic specialization, hippocampal neurons, synaptic plasticity, presynaptic plasma membrane
- MeSH terms
- Pentraxins, Animals, C-Reactive Protein, Hippocampus, Humans, Nerve Tissue Proteins, Neurons, Receptors, Cell Surface, Synapses, Receptors, AMPA, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, GABA Antagonists, Coculture Techniques, Excitatory Postsynaptic Potentials, RNA, Small Interfering, Mice, Gene Knockdown Techniques, HEK293 Cells
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