Pentraxins Coordinate Excitatory Synapse Maturation and Circuit Integration of Parvalbumin Interneurons
Open accessAbstract
Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2(-/-)/NPTXR(-/-) mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2(-/-)/NPTXR(-/-) mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2(-/-)/NPTXR(-/-) mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.
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NARP regulates PV neuron excitation through recruitment of glutamate (AMPA) receptors.
“neuronal pentraxin--2 (NARP) (Gu et al., 2013), which regulates PV neuron excitation through recruitment of glutamate (AMPA) receptors (Chang et al., 2010;Pelkey et al., 2015)”
From Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity (2016) · cites this paper as Pelkey et al., 2015
GluA4 clustering at excitatory synapses, particularly onto parvalbumin-positive interneurons, is mediated by extracellular neuronal pentraxins binding to the extracellular amino terminal domain.
“GluA4 clustering at excitatory synapses, particularly onto parvalbumin-positive interneurons, is mediated by the extracellular neuronal pentraxins which bind to the extracellular amino terminal domain, again highlighting the role of extracellular interactions in AMPAR synaptic recruitment (Pelkey et al., 2015, O'Brien et al., 1999, Sia et al., 2007).”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Pelkey et al., 2015
NPTXs regulate circuit rhythmogenesis and integration by controlling expression and synaptic localization of AMPAR and coordination of excitatory synapses maturation onto PV interneurons.
“NPTXs regulate circuit rhythmogenesis and integration by controlling expression and synaptic localization of AMPAR and coordination of excitatory synapses maturation onto PV interneurons (O’Brien et al. 1999; Pelkey et al. 2015).”
From Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration (2022) · cites this paper as Pelkey et al. 2015
Double knock-out (Nptx2−/−, Nptxr−/−) mice presented disrupted gamma oscillations and reduction of feedforward inhibition as a result of the reduction of one of the subunits of the AMPAR.
“In addition, the double KO (Nptx2−/−, Nptxr−/−) presented disrupted gamma oscillations and reduction of feedforward inhibition as a result of the reduction of one of the subunits of the AMPAR (Pelkey et al. 2015).”
From Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration (2022) · cites this paper as Pelkey et al. 2015
Endocannabinoid agonists suppress GDPs while antagonists increase their frequency, strongly implying the participation of CGE-derived CCK-containing interneurons.
“endocannabinoid agonists suppress GDPs while antagonists increase their frequency, strongly implying the participation of CGE-derived CCK-containing interneurons”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [886]
CGE-derived interneurons play a role in GDP generation.
“CGE-derived interneurons certainly play a role in GDP generation.”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [886]
Unlike mature hippocampal and cortical principal cells, which do not typically express GluA4, PV-containing interneurons possess a high level of GluA4 and a lower level of GluA2 subunit expression.
“Unlike mature hippocampal and cortical principal cells, which do not typically express GluA4, PV-containing interneurons possess a high level of GluA4 and a lower level of GluA2 subunit expression (388, 630, 886, 1242).”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [886]
GluA4 expression increases over the first two postnatal weeks to generate receptors comprised of GluA1/GluA4 heteromers by adulthood.
“GluA4 expression increases over the first two postnatal weeks to generate receptors comprised of GluA1/GluA4 heteromers by adulthood (99, 388, 800, 886).”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [886]
Immature synapses onto PV-containing interneurons lack GluA4 and are comprised of GluA1 homomers.
“However, immature synapses onto PV-containing interneurons lack GluA4 and are comprised of GluA1 homomers (886).”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [886]
The developmental upregulation of GluA4 in PV-containing interneurons requires the coordinated expression of both NPTX2 and NPTXR.
“In a subsequent study, the developmental upregulation of GluA4 in PV-containing interneurons was observed to require the coordinated expression of both NPTX2 and NPTXR (886).”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [886]
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- Authors
- Pelkey, K. A., Barksdale, E., Craig, M. T., Yuan, X., Sukumaran, M., Vargish, G. A., Mitchell, R. M., Wyeth, M. S., Petralia, R. S., Chittajallu, R., Karlsson, R.-M., Cameron, H. A., Murata, Y., Colonnese, M. T., Worley, P. F., & McBain, C. J.
- Affiliations
- National Institutes of Health (US)
- George Washington University (US)
- Johns Hopkins University (US)
- Corresponding author
- Pelkey, Kenneth A.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 85
- Issue
- 6
- Pages
- 1257-1272
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4368480
- OpenAlex
- W1971347175
- Cited by
- 245
- References
- 62
- Citations by year
- 2026: 17 · 2025: 30 · 2024: 28 · 2023: 14 · 2022: 11 · 2021: 33 · 2020: 33 · 2019: 17 · 2018: 23 · 2017: 16 · 2016: 18 · 2015: 5
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-05-04)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Open Research Exeter (University of Exeter) (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Figshare (submittedVersion)
- Funders
- National Institutes of Health (Z99HD999999)
- National Institute of Mental Health (P50MH100024)
- National Eye Institute (EY022730, R01EY022730)
- National Institute of Neurological Disorders and Stroke (NS 039156, R01NS039156)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (Z01HD001205)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- parvalbumin interneurons, fast-spiking interneurons, GluA4, AMPA receptors, NPTX2, pentraxins, synapse maturation, circuit integration, feedforward inhibition, giant depolarizing potentials, rhythmogenesis, epileptiform discharges, schizophrenia, postnatal development, excitation-inhibition balance
- MeSH terms
- Pentraxins, Action Potentials, Animals, Animals, Newborn, C-Reactive Protein, Disease Models, Animal, Interneurons, Nerve Net, Nerve Tissue Proteins, Parvalbumins, Synapses, Mice, Knockout, Mice
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