Human neurons express type I GnRH receptor and respond to GnRH I by increasing luteinizing hormone expression

Abstract

Gonadotropin-releasing hormone receptor I (GnRHR I) has been localized to the limbic system of the rat brain, although the functional consequences of GnRH signaling through these receptors is unknown. In this paper, we characterize the expression of GnRHR I in the human hippocampus and cortex, and the functionality of GnRHR I in human neuroblastoma cells. Robust GnRHR I immunoreactivity was detected in the cell body as well as along the apical dendrites of pyramidal neurons in the CA2, CA1, and end plate, but was clearly lower in the subiculum of the hippocampus. Immunolabeling was also evident in cortical neurons, including those located in the entorhinal cortex and occipitotemporal gyrus but was not observed within the granular layer of the dentate gyrus. No differences in immunohistochemical staining were observed between control and Alzheimer's disease brain. GnRHR I mRNA and protein (mature, immature, and other variant) expression was detected in human neuroblastoma cells (M17, SH-SY5Y) and rat embryonic primary neurons and varied with differentiation and GnRH treatment. Since GnRHR I was expressed by extrapituitary cells, and hypothalamic GnRH I secretion markedly increases post-menopause/andropause, we treated human M17 neuroblastoma cells cultured in serum-free conditions with GnRH I for 6 h and measured LH expression. M17 neuroblastoma cells express LHb mRNA, while immunoblot analysis indicated the presence of three LH variants (approximately 30, 47, and 60 kDa) that were upregulated by low concentrations of GnRH I, but downregulated at higher GnRH I concentrations. LH expression was also found to increase in differentiating embryonic rat primary cortical neurons. Our results demonstrate that neurons expressing GnRHR I are functional, responding to GnRH I by upregulating LH production. Post-reproductive surges in GnRH I secretion may explain the accumulation of LH in pyramidal neurons of the aged human and rat.

Development of the neurons controlling fertility in humans: new insights from 3D imaging and transparent fetal brains

“…These mapping experiments have revealed the wide distribution of GnRH cells and terminals in several extrahypothalamic regions. These observations raise the intriguing possibility that GnRH signals to GnRH receptor-expressing neuronal populations dispersed in several brain regions (Granger et al, 2004;Wilson et al, 2006) to modulate as yet unexplored nonreproductive functions, such as the recently proposed regulation of systemic aging (Zhang et al, 2013). Notably, in addition to the extensive GnRH fiber distribution in those areas, GnRH is also present in the cerebrospinal fluid at concentrations proportional to those detected in the portal blood vessels (Van Vugt et al, 1985) and might thus represent an additional source of GnRH that could potentially signal to multiple brain regions.…”

The Relationship Between Estrogen and the Decline in Delta Power During Adolescence

“…In CPP, premature activation of the hypothalamic GnRH neuronal network is the inciting event, stimulating pituitary secretion of FSH and LH, which then trigger ovarian estrogen production. While the GnRH neuropeptide has traditionally been thought to be confined to the hypothalamic median eminence, the identification of the GnRH peptide 31 and the GnRH receptor 32 in human cerebral cortex indicates the potential for extra-hypothalamic functions.…”

“…CPP participants and study controls demonstrated a similar distribution of chronotype scores, with the average score in both groups falling within the "intermediate" category, defined as scores of 24-32 (CPP: 27.5 ± 1.7 ; controls: 25.2 ± 3.1 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]). Suppressive therapy with a GnRHa and/or the passage of time had no effect on CPP participants' morningness/ eveningness preference, and chronotype did not correlate with chronologic age or stage of breast development in combined analyses of CPP participants and study controls (r = −0.06, p > .05 for both tests).…”

Physiology of Gonadotropin-Releasing Hormone (Gnrh): Beyond the Control of Reproductive Functions

“…Actually, studies using GnRHa leuprolide therapy, aimed at down regulating peripheral LH, show a decrease the toxic Ab load in the brain and a significant improvements in cognitive performance. 33,37,39 Animal studies utilizing GnRHR antagonists, (cetrorelix), which also lowers serum levels of LH, also show cognitive improvements. 40 More recently, it has been reported a higher hippocampal level of GnRH and GnRHR mRNA in both male and female plaque-bearing AD transgenic mice (tgArcSwe), respect to age matched controls.…”