Developmental regulation of the NMDA receptor subunits, NR3A and NR1, in human prefrontal cortex
Open accessAbstract
Subunit composition of N-methyl-D-aspartate-type glutamate receptors (NMDARs) dictates their function, yet the ontogenic profiles of human NMDAR subunits from gestation to adulthood have not been determined. We examined NMDAR mRNA and protein development in human dorsolateral prefrontal cortex (DLPFC), an area in which NMDARs are critical for higher cognitive processing and NMDAR hypofunction is hypothesized in schizophrenia. Using quantitative reverse transcriptase-polymerase chain reaction and western blotting, we found NR1 expression begins low prenatally, peaks in adolescence, yet remains high throughout life, suggesting lifelong importance of NMDAR function. In contrast, NR3A levels are low during gestation, surge soon after birth, and decline progressively through adolescence and into adulthood. Because NR3A subunits uniquely attenuate NMDAR-mediated currents, limit calcium influx, and suppress dendritic spine formation, high levels during early childhood may be important for regulating neuroprotection and activity-dependent sculpting of synapses. We also examined whether subunit changes underlie reduced NMDAR activity in schizophrenia. Our results reveal normal NR1 and NR3A protein levels in DLPFC from schizophrenic patients, indicating that NMDAR hypofunction is unlikely to be maintained by gross changes in NR3A-containing NMDARs or overall NMDAR numbers. These data provide insights into NMDAR functions in the developing CNS and will contribute to designing pharmacotherapies for neurological disorders.
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In humans, mRNA and protein expression of the obligatory subunit of the NMDA receptor, NR1, peaks within the frontal cortex in the 11-15 year old age group before declining until age 21-25.
“In humans, mRNA and protein expression of the obligatory subunit of the NMDA receptor, NR1, peaks within the frontal cortex in the 11–15 year old age group before declining until age 21–25 (Catts et al., 2013; Henson et al., 2008).”
From Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? (2017) · cites this paper as Henson et al., 2008
NMDA receptor expression changes during peripubertal development.
“NMDA receptor expression also changes during peripubertal development.”
From Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex? (2017) · cites this paper as Henson et al., 2008
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Adolescence as a neurobiological critical period for the development of higher-order cognition
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“NR3A levels are low in embryonic day, increases rapidly after birth and declines gradually into adulthood [7].”
BackgroundEmerging roles of GluN3-containing NMDA receptors in the CNS
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Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?
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- Authors
- Henson, M. A., Roberts, A. C., Salimi, K., Vadlamudi, S., Hamer, R. M., Gilmore, J. H., Jarskog, L. F., & Philpot, B. D.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- New York State Psychiatric Institute (US)
- Venue
- Cerebral Cortex
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-02-21
- Volume
- 18
- Issue
- 11
- Pages
- 2560-2573
- ISSN
- 1047-3211 (ISSN-L)
- 1460-2199
- PMC
- PMC2733318
- OpenAlex
- W2166442546
- Cited by
- 110
- References
- 132
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 4 · 2023: 7 · 2022: 6 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 8 · 2015: 7 · 2014: 3 · 2013: 7 · 2012: 7
- FWCI
- 3.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cerebral Cortex (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- UNC Libraries
- Funders
- National Alliance for Research on Schizophrenia and Depression
- University of North Carolina at Chapel Hill
- National Institute of Mental Health (MH064065, P50MH064065)
- National Eye Institute (R01EY018323)
- National Institute of General Medical Sciences (R25GM055336)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- NMDA receptor, NR1 subunit, ontogeny, schizophrenia, NMDA receptor hypofunction, dendritic spine formation, calcium influx, neuroprotection, synaptogenesis, prenatal development
- MeSH terms
- Adolescent, Adult, Aged, Animals, Child, Child, Preschool, Fetus, Humans, Infant, Infant, Newborn, Male, Mice, Inbred C57BL, Middle Aged, Schizophrenia, Antipsychotic Agents, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Prefrontal Cortex, Gene Expression Regulation, Developmental, Mice, Rats, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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