A Specific Role for NR2A-Containing NMDA Receptors in the Maintenance of Parvalbumin and GAD67 Immunoreactivity in Cultured Interneurons
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Several lines of evidence suggest that a hypoglutamatergic condition may induce a phenotypic loss of cortical parvalbumin (PV)-positive GABAergic interneurons, such as that observed in brain tissue of schizophrenic subjects. However, it is not known whether the loss of PV interneurons is a consequence of the hypoglutamatergic condition or a secondary aspect of the disease. We characterized the signaling and subunit expression of NMDA receptors in cultured cortical PV interneurons and determined whether a hypoglutamatergic condition, created by direct application of sublethal concentrations of ketamine or subunit-selective NMDA receptor antagonists, can affect the expression of the GABAergic markers as observed in vivo. Real-time PCR performed on mRNA isolated from single neurons showed that PV interneurons present a fivefold higher NR2A/NR2B ratio than pyramidal neurons. Brief, nontoxic, exposure to NMDA led to an increase in ERK1/2 (extracellular signal-regulated kinase 1/2) and cAMP response element-binding protein phosphorylation in PV interneurons, and this increase was blocked by the NR2A-selective antagonist NVP-AAM077. Application of the nonselective NMDA receptor antagonist ketamine, at sublethal concentrations, induced a time and dose-dependent decrease in parvalbumin and GAD67 immunoreactivity specifically in PV interneurons. These effects were reversible and were also observed with the NR2A-selective antagonist, whereas the NR2B-selective antagonist Ro-25-6981 only partially reduced GAD67 immunoreactivity. Coexposure to the calcium channel opener BayK, or the group I metabotropic glutamate receptor agonist DHPG [(RS)-3,5-dihydroxyphenylglycine] attenuated the decrease in GAD67 and parvalbumin induced by the NMDA receptor antagonists. These results suggest that the activity of NR2A-containing NMDA receptors play a pivotal role in the maintenance of the GABAergic function of PV interneurons.
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Parvalbumin levels and perineuronal net labeling are regulated in an activity-dependent manner.
“Levels of PV (Kinney et al, 2006) and PNN labeling (Dityatev et al, 2007;Giamanco and Matthews, 2012) are regulated in an activity-dependent manner.”
From Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia (2016) · cites this paper as Kinney et al, 2006
The maturation of parvalbumin interneurons is activity-dependent; calcium entry is necessary for maturation of perineuronal nets and parvalbumin interneurons, and activation of NR2A-containing NMDARs contributes to the molecular signaling that leads to maturation of these cells.
“Indeed, the maturation of PVI is activity-dependent (Chattopadhyaya et al., 2004; Patz et al., 2004). Calcium entrance is necessary for the maturation of PNN (Dityatev et al., 2007) and PVI (Jiang and Swann, 2005; Kinney et al., 2006), and activation of NR2A-containing NMDARs contributes to the molecular signaling that leads to the maturation of these cells (Kinney et al., 2006; Zhang and Sun, 201”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Kinney et al., 2006
The GluN2A subunit is primarily expressed in PV interneurons.
“the GluN2A subunit is primarily expressed in PV interneurons (Kinney et al., 2006”
From Neuronal Dynamics and Neuropsychiatric Disorders: Toward a Translational Paradigm for Dysfunctional Large-Scale Networks (2012) · cites this paper as Kinney et al., 2006
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References 71 · Cited by 329
- Authors
- Kinney, J. W., Davis, C. N., Tabarean, I., Conti, B., Bartfai, T., & Behrens, M. M.
- Affiliations
- Scripps Research Institute (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-02-01
- Volume
- 26
- Issue
- 5
- Pages
- 1604-1615
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6675509
- OpenAlex
- W2013209042
- Cited by
- 329
- References
- 71
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 8 · 2023: 12 · 2022: 6 · 2021: 19 · 2020: 14 · 2019: 12 · 2018: 20 · 2017: 14 · 2016: 14 · 2015: 15 · 2014: 21 · 2013: 25 · 2012: 25
- FWCI
- 5.95
- 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 Alliance for Research on Schizophrenia and Depression
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- NMDA receptor, NR2A subunit, parvalbumin interneurons, GAD67, GABAergic interneurons, ketamine, NVP-AAM077, Ro 25-6981, ERK1/2, CREB phosphorylation, metabotropic glutamate receptors, DHPG, Bay K 8644, schizophrenia, cortical interneurons, glutamatergic signaling
- MeSH terms
- Animals, Calcium, Cells, Cultured, Glutamate Decarboxylase, Immunohistochemistry, Interneurons, Isoenzymes, Ketamine, Parvalbumins, Phosphorylation, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Prosencephalon, Cyclic AMP Response Element-Binding Protein, Patch-Clamp Techniques, Excitatory Amino Acid Antagonists, Extracellular Signal-Regulated MAP Kinases, Mice
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