Expression of Glutamate Receptor Subunits in the Hypothalamus of the Female Rat during the Afternoon of the Proestrous Luteinizing Hormone Surge and Effects of Antiprogestin Treatment and Aging

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Abstract

The excitatory transmitter, glutamate has been implicated in the control of reproduction, hormone secretion and neuroendocrine regulation. The present study examined whether the hypothalamic expression of three key ionotropic glutamate receptor subunits (NMDAR1, GluR1 and GluR6) fluctuates significantly on proestrus in the rat, and whether treatment with the antiprogestin, RU486 affected glutamate receptor subunit expression. The studies revealed that NMDAR1, GluR1 and GluR6 mRNA levels in the mediobasal hypothalamus (MBH) and preoptic area (POA) fluctuate little throughout the day of proestrus. However, treatment with the antiprogestin, RU486 induced a significant elevation of GluR6 mRNA levels at 14.00 and 16.00 h on proestrus in the MBH, suggesting that endogenous progesterone (P4) may act to inhibit hypothalamic GluR6 levels. In support of this suggestion, exogenous P4 treatment to estrogen (E2)-primed ovariectomized (ovx) rats significantly suppressed GluR6 mRNA levels in the afternoon (12.00–16.00 h) in the MBH, and at 12.00 h in the POA, which preceded LH surge induction. Likewise, temporal examination of hypothalamic GluR6 protein levels in E2 + P4-treated young and middle-aged ovx rats revealed an early elevation from 12.00 to 14.00 h, which was followed by a fall from 16.00 to 20.00 h. The early elevation of GluR6 protein levels was most pronounced in the POA of the young rat, and this elevation was markedly attenuated in the middle-aged rat. As a whole, the studies suggest that glutamate receptor expression fluctuates little on proestrus in the hypothalamus, but that expression of the kainate GluR6 receptor subunit may be modulated by progesterone and aging.

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Most cited references 29

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Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice.

Christophe Mulle, Andreas Sailer, Isabel Pérez-Otaño … (1998)

L-glutamate, the neurotransmitter of the majority of excitatory synapses in the brain, acts on three classes of ionotropic receptors: NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptors. Little is known about the physiological role of kainate receptors because in many experimental situations it is not possible to distinguish them from AMPA receptors. Mice with disrupted kainate receptor genes enable the study of the specific role of kainate receptors in synaptic transmission as well as in the neurotoxic effects of kainate. We have now generated mutant mice lacking the kainate-receptor subunit GluR6. The hippocampal neurons in the CA3 region of these mutant mice are much less sensitive to kainate. In addition, a postsynaptic kainate current evoked in CA3 neurons by a train of stimulation of the mossy fibre system is absent in the mutant. We find that GluR6-deficient mice are less susceptible to systemic administration of kainate, as judged by onset of seizures and by the activation of immediate early genes in the hippocampus. Our results indicate that kainate receptors containing the GluR6 subunit are important in synaptic transmission as well as in the epileptogenic effects of kainate.

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Excitatory amino acids: function and significance in reproduction and neuroendocrine regulation.

Darrell W. Brann, H V Mahesh (1994)

Excitatory amino acid neurotransmission is an essential component of the neuroendocrine transmission line that regulates anterior pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Excitatory amino acids (EAAs), such as glutamate and aspartate, are found in large concentrations in presynaptic boutons of a variety of important hypothalamic nuclei, including the arcuate nucleus, the suprachiasmatic nucleus, the supraoptic nucleus, the paraventricular nucleus, and the preoptic area. EAA receptors can be divided into two broad groups, namely, ionotropic and metabotropic receptors. Ionotropic receptors are subdivided into NMDA (N-methyl-D-aspartate), kainate, and AMPA (DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Their main mode of action is by the modulation of Na+, K+, and Ca2+ ion channels. Metabotropic receptors, on the other hand, act by a G-protein-stimulated release of intracellular Ca2+ or modulation of adenylate cyclase activity. The different EAA receptor subtypes are found in a variety of areas of the hypothalamus and the brain. In a variety of species, the administration of glutamate, NMDA, or kainate leads to LH release mediated through the stimulation of hypothalamic gonadotropin hormone-releasing hormone (GnRH) release. The major site of NMDA action appears to be the preoptic area--where GnRH cell bodies reside. AMPA and kainate appear to act primarily at the arcuate nucleus/median eminence, the site of GnRH nerve terminals. NMDA may also act upon noradrenergic neurons in the locus coeruleus to influence hypothalamic GnRH release. The steroid-induced LH surge in ovariectomized animals and the preovulatory surge of LH in cycling animals and in pregnant mare's serum gonadotropic-primed animals are blocked by the NMDA antagonist MK801 and the AMPA/kainate antagonist DNQX. MK801 also suppressed FSH surges in most instances, whereas DNQX had no effect on FSH surges. In the ovariectomized female rat, both the NMDA antagonist AP5 and the AMPA/kainate antagonist DNQX, lowered mean LH levels, LH pulse amplitude, and LH pulse frequency. Activation of NMDA receptors advanced the time of vaginal opening in the immature female rat, while kainate and DNQX were without effect. Gonadal steroid removal (castration) did not alter NMDA receptor levels or affinity in the hypothalamus of female or male rats. Likewise, steroid replacement to castrate rats did not affect hypothalamic NMDA receptor levels or NMDA R1 mRNA levels. Similarly, NMDA and kainate receptor levels in the hypothalamus did not change during the time of puberty in the female rat. In contrast, AMPA receptor (GluR1) immunoreactive levels in the magnocellular preoptic area (mPOA), the arcuate nucleus (ARC), and the suprachiasmatic nucleus (SCN) were found to be markedly elevated during the time of the LH surge in estradiol-progesterone-treated castrate rats compared to those of the vehicle-only-treated castrate rat. The release rates of glutamate and aspartate in the POA were found to be significantly elevated during the steroid-induced LH surge in the ovariectomized adult rat.(ABSTRACT TRUNCATED AT 400 WORDS)

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Ionotropic glutamate-receptor gene expression in hypothalamus: localization of AMPA, kainate, and NMDA receptor RNA with in situ hybridization.

S. Heinemann, P. Ghosh, I Hermans-Borgmeyer … (1994)

In situ hybridization and Northern blots were used to study the ionotropic subtypes of the glutamate receptor in the rat hypothalamus. Widespread expression of AMPA, kainate, and NMDA receptor RNA was found in the hypothalamus with the transcripts the same size and number as found in other regions of the brain. Most of the glutamate-receptor subunits studied were expressed in greater amounts in hippocampus than in hypothalamus; GluR5, on the other hand, showed a greater expression in hypothalamus than in hippocampus. On the basis of Northern blot analysis, all regions of the brain examined, including hypothalamus, cerebral cortex, cerebellum, olfactory bulb, and hippocampus, expressed all eight of the subunits studied. Each subunit showed different relative expressions in the different regions. In the hypothalamus, GluR1 and GluR2 were among the most widely expressed of the non-NMDA ionotropic receptors. Other AMPA-preferring receptors, GluR3 and -R4, were also found, but to a lesser extent. Scattered cells expressed the kainate-preferring receptors GluR5, -R6, and -R7. The NMDA receptor NMDAR1 was detected throughout the hypothalamus. In many regions of the hypothalamus, only scattered cells showed detectable expression of the glutamate-receptor mRNA as detected by autoradiographic silver grains over neurons; unlabeled cells were mixed among labeled cells. Every region of the hypothalamus had several different glutamate receptors. The expression of many different types of ionotropic glutamate receptors throughout the hypothalamus suggests that multiple modes of ion channel regulation by glutamate probably operate here and provides further support for the importance of the excitatory transmitter glutamate in hypothalamic regulation.

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Author and article information

Journal

Journal ID (publisher-id): NEN

Journal ID (nlm-ta): Neuroendocrinology

Journal ID (doi): 10.1159/issn.0028-3835

Title: Neuroendocrinology

Publisher: S. Karger AG

ISSN (Print): 0028-3835

ISSN (Electronic): 1423-0194

Publication date Subscription-year: 2005

Publication date (Print): July 2005

Publication date (Electronic): 06 July 2005

Volume: 81

Issue: 2

Pages: 120-128

Affiliations

Institute of Molecular Medicine and Genetics, Department of Neurology, Program in Developmental Neurobiology, School of Medicine, Medical College of Georgia, Augusta, Ga., USA

Article

Publisher ID: 86405 Other ID: Neuroendocrinology 2005;81:120–128

DOI: 10.1159/000086405

PubMed ID: 15961958

SO-VID: df95972a-6803-4d41-b560-a5e7c5427a7c

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