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Vol. 68, No. 2, 1998
Issue release date: August 1998
Section title: Regulation of Hypothalamic Neurons
Neuroendocrinology 1998;68:77–88
(DOI:10.1159/000054353)

Exogenous Glutamate Enhances Glutamate Receptor Subunit Expression during Selective Neuronal Injury in the Ventral Arcuate Nucleus of Postnatal Mice

Hu L.a · Fernstrom J.D.b · Goldsmith P.C.a
a Reproductive Endocrinology Center, Department of Ob/Gyn and Reproductive Sciences, University of California, San Francisco, Calif., and b Departments of Psychiatry, Pharmacology and Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pa., USA

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Article / Publication Details

First-Page Preview
Abstract of Regulation of Hypothalamic Neurons

Published online: 8/21/1998
Issue release date: August 1998

Number of Print Pages: 12
Number of Figures: 0
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: http://www.karger.com/NEN

Abstract

Administration of high doses of glutamate (Glu) leads to selective neurodegeneration in discrete brain regions near circumventriclular organs of the early postnatal mouse. The arcuate nucleus-median eminence complex (ARC-ME) appears to be the most Glu-sensitive of these brain regions, perhaps because of the intimate relationships between its neurons and specialized astroglial tanycytes. To investigate the mechanism of Glu-induced neuronal loss, we administered graded doses of the sodium salt of glutamate (MSG) to postnatal mice, measured their plasma Glu concentrations, and performed microscopic analyses of the ARC-ME region 5 h after treatment. Nursing, 7-day-old mouse pups (CD1, Charles River, Hollister, Calif.) were injected subcutaneously with single doses of 0.1–0.5 or 1.0–4.0 mg of MSG per g BW, or with water vehicle alone. Mice were decapitated 5 h later and the brains immediately fixed by immersion in buffered aldehydes. Frontal vibratome tissue sections at comparable levels of the ARC-ME were examined by light microscopy. A dose of 4.0 mg MSG/g BW caused neurodegeneration throughout the ARC region, while 1.0 mg/g MSG resulted in less extensive damage. Injection of 0.2 mg MSG/g BW, which raised plasma Glu concentrations 17-fold after 15 min, was the minimum dose tested at which nuclear and cytoplasmic changes were observed in a small group of subependymal neurons near the lateral recesses of the third ventricle. Higher doses of 0.3–0.5 mg MSG caused injury to additional neurons situated farther laterally, but damage remained confined to the ventral region of the ARC nucleus. Ultrastructural examination showed some subependymal neurons with pyknotic nuclei, reduced cytoplasmic volume, and swollen subcellular organelles, while others had fragmented and condensed nuclear material. Immunostaining for tyrosine hydroxylase indicated that dopamine neurons were spared at the threshold dose, but suffered damage after higher doses of MSG. Immunostaining for Glu receptor subtypes revealed that 0.2 mg MSG/g BW enhanced neuronal expression of NMDAR1 and of GluR2/4, and that higher doses of MSG preferentially increased NMDAR1 expression in injured neurons. These results extend previous reports of Glu sensitivity in the ARC-ME region of 7-day postnatal mice. A dose of 0.2 mg MSG/g BW s.c. causes clear but discrete injury to specific subependymal neurons of undetermined phenotype near the base of the third ventricle. Slightly higher doses of MSG evoke damage of additional neurons confined to the ventral region of the ARC traversed by tanycytes. These same greater amounts of MSG promote dose-related increase in the expression of NMDAR1 more than of GluR2/4 in injured ARC neurons, suggesting that elevated Glu receptor levels may contribute to or be related to neuronal cell death. Taken together with previous findings, the data suggest that Glu responsitivity in the ARC-ME of the postnatal mouse may result from transient developmental conditions involving the numerical ratios and juxtaposition between tanycytes and neurons, expression of Glu receptors, and perhaps other ontogenetic factors which may not persist in the mature adult.


  

Author Contacts

Paul C. Goldsmith
Reproductive Endocrinology Center
Department of Ob/Gyn and Reproductive Sciences, University of California, San Francisco
San Francisco, CA 94143-0556 (USA)
Tel. +1 415 476 3995, Fax +1 415 753 3271, E-Mail paul_goldsmith@quickmail.ucsf.edu

  

Article Information

Received: Received: October 30, 1997
Accepted after revision: May 5, 1998
Number of Print Pages : 12
Number of Figures : 6, Number of Tables : 0, Number of References : 41

  

Publication Details

Neuroendocrinology (International Journal for Basic and Clinical Studies on Neuroendocrine Relationships)
Founded 1965 by E. Bajusz. Continued by K.M. Knigge (1973–1978), W.F. Ganong (1979–1984), S.M. McCann (1985–1993)
Official Journal of the International Society of Neuroendocrinology

Vol. 68, No. 2, Year 1998 (Cover Date: August 1998)

Journal Editor: C. Kordon, Paris
ISSN: 0028–3835 (print), 1423–0194 (Online)

For additional information: http://www.karger.com/journals/nen


Article / Publication Details

First-Page Preview
Abstract of Regulation of Hypothalamic Neurons

Published online: 8/21/1998
Issue release date: August 1998

Number of Print Pages: 12
Number of Figures: 0
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: http://www.karger.com/NEN


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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