Expression of Glutamate Receptor Subunit mRNAs in Gonadotropin-Releasing Hormone Neurons during the Sexual Maturation of the Female Rat

Abstract

Excitatory amino acids, particularly glutamate, are thought to be important for the maturation of the brain-pituitary-gonadal axis and the induction of puberty in the rat. We have previously shown that, in the female rat, GnRH neurons preferentially express the KA2 and NMDAR2A receptor subunit mRNAs, but not AMPA or NMDAR1 mRNA. The aim of the present study was to determine whether the onset or rate of KA2 and NMDAR2A receptor expression in GnRH neurons is correlated with the onset of puberty. Dual in situ hybridization using digoxigenin-labeled GnRH cRNA probes and ³⁵S-labeled glutamate receptor subunit probes, followed by autoradiography and image analysis were used to measure the KA2 or NMDAR2A mRNA content in GnRH neurons in 20- to 50-day-old female rats which were sacrificed at 08.00 or 17.00 h. The results show that: (a) the KA2 mRNA content of GnRH neurons and the number of GnRH neurons expressing KA2 mRNA increase progressively in the morning hours between postnatal days 20 and 40; (b) the diurnal pattern of KA2 mRNA levels in GnRH neurons changes between days 40 and 50 from high KA2 levels in the morning hours before day 40 to high KA2 mRNA levels in the afternoon in 45- and 50-day-old animals; (c) while the high levels of KA2 mRNA in GnRH neurons in the morning hours of 20-to 40-day-old animals are paralleled by an overall increase in KA2 expression in the preoptic area, the rise in KA2 mRNA in GnRH neurons in the afternoon of 45- and 50-day-old animals appears to be specific for the GnRH neurons, and (d) no significant differences were detected for the NMDAR2A mRNA content in GnRH neurons among the different age groups and the morning and afternoon values. Since the gradual increase in the KA2 mRNA content in GnRH neurons of animals reaching puberty as well as the reversal of diurnal rhythmicity in KA2 receptor mRNA content of GnRH neurons coincide with the times of vaginal opening and first ovulation, it is suggested that glutamate, acting through KA2 receptors directly on GnRH neurons is, at least in part, an important factor in the excitatory regulation of the postnatal sexual development of the female rat. In contrast, expression of the NMDA-preferring receptor, NMDAR2A, in GnRH neurons appeared to be unchanged during this development.

The adolescent brain and age-related behavioral manifestations

“…Administration of the glutamate agonist NMDA induces precocious puberty in rats and nonhuman primates [57,428], while the antagonists MK-801 [563] and phencyclidine [501] delay puberty. Opinions differ as to whether this effect is mediated by kainate [161], NMDA, or dl-aamino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) [607] forms of the glutamate receptor [57], although stimulation of each receptor type has been shown to facilitate GnRH release [74,425]. Glutamate may not only stimulate GnRH release directly, but also indirectly via stimulating the release of the prostaglandin PGE 2 by local astrocytes, with this PGE 2 also facilitating GnRH release [389].…”

Physiologic Regulation of a Tetrodotoxin-Sensitive Sodium Influx That Mediates a Slow Afterdepolarization Potential in Gonadotropin-Releasing Hormone Neurons: Possible Implications for the Central Regulation of Fertility

“…We first examined synaptic mechanisms by testing the effects of blocking the receptors for a variety of neurotransmitters and neuromodulators thought to be key inputs to GnRH neurons. GnRH neurons are spiny (Witkin, 1989;Campbell et al, 2005) and express functional iGluRs (Brann and Mahesh, 1994;Eyigor and Jennes, 1997;Adams et al, 1999;Suter, 2004). Recent evidence indicates that they express vesicular glutamate transporter 2 (Hrabovszky et al, 2004) and are functionally glutamatergic (Chu and Moenter, 2005).…”

Hypothalamic Tumor Necrosis Factor-α Converting Enzyme Mediates Excitatory Amino Acid-Dependent Neuron-to-Glia Signaling in the Neuroendocrine Brain

“…They act via NMDA and AMPA/kainate receptors expressed in both LHRH neurons and interneurons connected to the LHRH neuronal network (Gore et al, 1996;Eyigor and Jennes, 1997;Eyigor and Jennes, 2000;Ottem et al, 2002). Notwithstanding the importance of this trans-synaptic control, it recently became evident that glutamatergic neurons can also control astrocytic function, and therefore LHRH release, via facilitation of erbB-dependent glia-to-neuron signaling pathways .…”