N-Methyl-d-Aspartate Receptor Subunit Expression in GnRH Neurons Changes during Reproductive Senescence in the Female Rat

Miller, Brooke H.; Gore, Andrea C.

doi:10.1210/en.2002-220346

Cited by 59Hypothalamic control of reproductive hormonesNeuroscience and Neuropharmacology ResearchReproductive Biology and Fertility

N-Methyl-d-Aspartate Receptor Subunit Expression in GnRH Neurons Changes during Reproductive Senescence in the Female Rat

Miller, Brooke H., Gore, Andrea C.·2002·Endocrinology

DOI 10.1210/en.2002-220346

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Abstract

During reproductive senescence in females, the function of GnRH neurons becomes compromised, and this may play a role in the transition from normal estrous cycles to acyclicity. One hypothalamic component of this dysregulation is an alteration in the stimulatory effects of glutamate, acting via N-methyl-D-aspartate receptors (NMDARs), on GnRH release. The present study examined whether GnRH neurons express the subunits necessary to make functional NMDARs, and how subunit expression may change during aging in association with compromised reproductive physiology. Colocalization of the three NMDAR subunits that are most abundant in the hypothalamus (NR1, NR2A, or NR2B) with GnRH perikarya was determined in female rats at different stages of the reproductive life cycle: young (3-4 months) rats with regular estrous cycles, middle-aged (8-10 months) rats with regular estrous cycles, middle-aged rats with irregular estrous cycles, and middle-aged acyclic rats in persistent estrus. The number, percent, and localization of GnRH perikarya expressing NR1, NR2A, or NR2B were mapped and quantified by double label immunofluorescence microscopy. Overall, each of the NMDAR subunits was present in a majority of GnRH neurons. There were no age- or reproductive status-related changes in coexpression of NR1 or NR2A subunits in GnRH neurons. However, coexpression of the NR2B subunit, which affects several functional channel characteristics, was significantly lower in young compared with middle-aged rats, irrespective of reproductive status. This may result in an age-related increase in the ratio of the NR2B to the NR1 and NR2A subunits on GnRH neurons. These data indicate that the majority of GnRH neurons express the proteins needed to receive direct NMDAR-mediated glutamatergic input, and that a change in the stoichiometry of the NMDAR pentamer occurs during aging that precedes, and may have consequences for, altered neuroendocrine function.

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GnRH and kisspeptin neurons express various glutamate and GABA receptors and respond to these neurotransmitters.
“Even though estradiol is considered the main regulator of gonadotropin release, GnRH and kisspeptin neurons express various glutamate and GABA receptors and respond to these neurotransmitters [100,101].”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [100]

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Neuroendocrine Aging in the Female Rat: The Changing Relationship of Hypothalamic Gonadotropin-Releasing Hormone Neurons and N-Methyl-D-Aspartate Receptors
Gore, A. C. (2000) · Endocrinology · doi:10.1210/en.141.12.4757 · Cited by 24 · see citing works
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Printed in U.S.A. Copyright © 2000 by The Endocrine Society Neuroendocrine Aging in the Female Rat: The Changing Relationship of Hypothalamic Gonadotropin-Releasing Hormone Neurons and N-Methyl-D-Aspartate Receptors*
Gore, A. C., Yeung, G., Morrison, J. H., & Oung, T. (2013)
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Neuroendocrine Aging in the Female Rat: The Changing Relationship of Hypothalamic Gonadotropin-Releasing Hormone Neurons and N-Methyl-d-Aspartate Receptors**Preliminary versions of this work were presented at the 28th and 29th Annual Meetings of the Society for Neuroscience (Abstracts 110.11 and 777.10). This work was supported by the Brookdale Foundation (to A.C.G.), NIH Grant 1-PO1-AG16765–01 (to A.C.G. and J.H.M.).
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Self-citation
Age‐ and Hormone‐Regulation of N‐Methyl‐ d ‐Aspartate Receptor Subunit NR2b in the Anteroventral Periventricular Nucleus of the Female Rat: Implications for Reproductive Senescence
Maffucci, J. A., Noel, M. L., Gillette, R., Wu, D., & Gore, A. C. (2009) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2009.01860.x · Cited by 21 · see citing works
Self-citation
Gonadotropin-releasing hormone neurons, NMDA receptors, and their regulation by steroid hormones across the reproductive life cycle
Gore, A. C. (2001) · Brain Research Reviews · doi:10.1016/s0165-0173(01)00121-7 · Cited by 84 · see citing works
Self-citation

Authors: Miller, B. H., & Gore, A. C.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
Corresponding author: Gore, Andrea C.
ORCID: Gore, Andrea C.
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2002-09
Volume: 143
Issue: 9
Pages: 3568-3574
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2002-220346
OpenAlex: W2165018640
Cited by: 59
References: 50
Citations by year: 2025: 1 · 2024: 2 · 2022: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 1 · 2014: 4 · 2013: 2 · 2012: 2
FWCI: 4.40
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (P01 AG16765, P01AG016765)
Topics: Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords: NMDA receptor subunits, GnRH neurons, reproductive aging, female reproductive aging, NR2B subunit, NR1 subunit, NR2A subunit, glutamatergic input, hypothalamus, estrous cycle, acyclicity, persistent estrus, neuroendocrine dysfunction, receptor stoichiometry
MeSH terms: Aging, Animals, Cell Count, Female, Fluorescent Antibody Technique, Gonadotropin-Releasing Hormone, Microscopy, Fluorescence, Neurons, Preoptic Area, Reproduction, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Rats

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N-Methyl-d-Aspartate Receptor Subunit Expression in GnRH Neurons Changes during Reproductive Senescence in the Female Rat

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