Modulation of Gonadotropin-Releasing Hormone Neuron Activity and Secretion in Mice by Non-peptide Neurotransmitters, Gasotransmitters, and Gliotransmitters

Abstract

Gonadotropin-releasing hormone (GnRH) neuron activity and GnRH secretion are essential for fertility in mammals. Here, I review findings from mouse studies on the direct modulation of GnRH neuron activity and GnRH secretion by non-peptide neurotransmitters (GABA, glutamate, dopamine, serotonin, norepinephrine, epinephrine, histamine, ATP, adenosine, and acetylcholine), gasotransmitters (nitric oxide and carbon monoxide), and gliotransmitters (prostaglandin E2 and possibly GABA, glutamate, and ATP). These neurotransmitters, gasotransmitters, and gliotransmitters have been shown to directly modulate activity and/or GnRH secretion in GnRH neurons in vivo or ex vivo (brain slices), from postnatal through adult mice, or in embryonic or immortalized mouse GnRH neurons. However, except for GABA, nitric oxide, and prostaglandin E2, which appear to be essential for normal GnRH neuron activity, GnRH secretion, and fertility in males and/or females, the biological significance of their direct modulation of GnRH neuron activity and/or GnRH secretion in the central regulation of reproduction remains largely unknown and requires further exploration.

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

“…However, despite an overall downregulation of Gad1 in the hypothalamus of Prdm13 -deficient mice, the expression of typical hypothalamic GABAergic neuronal markers was unaltered. Yet given that GABAergic neurotransmission at the hypothalamic level is on its own fundamental in sustaining fertility and pubertal onset ( 43 ), reduced levels of GABA might also contribute to CHH observed in the patients.…”

“…Npvf expression appeared slightly reduced but this difference was not significant (Figure 3B). Because PRDM13 is known to control GABAergic neuronal cell fate in several brain areas (33)(34)(35), and GABAergic neurotransmission plays important roles to sustain fertility (43), we also analyzed Gad1 expression and found a significant decrease of Gad1 levels in Prdm13 -/mice compared to Prdm13 +/+ mice (Figure 3C). However, the expression of typical GABAergic hypothalamic neuronal markers such as Pomc and Npy/Agrp (44), was similar in Prdm13 -/and Prdm13 +/+ mice (Supplemental Figure 2A), suggesting that only a subset of hypothalamic neurons requires PRDM13.…”

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

“…Our data highlight that PRDM13 selectively controls a subset of hypothalamic neurons, underlining a cell-specific role of PRDM13 in the differentiation program of the hypothalamus. In contrast, despite an overall downregulation of Gad1 in the hypothalamus of Prdm13-deficient mice, the expression of typical hypothalamic GABAergic neuronal markers was unaltered Yet, given that GABAergic neurotransmission at the hypothalamic level is on its own fundamental in sustaining fertility and pubertal onset (45), reduced levels of GABA might also contribute to CHH observed in the patients. Interestingly and in contrast to Ptf1a-deficient mice, our data also indicate that Prdm13 deficiency specifically affects Kiss1 neurons in the Arc nucleus, but not in the AVPV, suggesting a highly restrictive role for PRDM13 in the specification of Arc Kiss1 neurons and the possible involvement of additional transcription factors in the specification of AVPV Kiss1 neurons.…”

“…Npvf expression appeared slightly reduced but this difference was not significant (Figure 3B). Because PRDM13 is known to control GABAergic neuronal cell fate in several brain areas (35)(36)(37), and GABAergic neurotransmission plays important roles to sustain fertility (45), we also analyzed Gad1 expression and found a significant decrease of Gad1 levels in Prdm13 -/mice compared to Prdm13 +/+ mice (Figure 3C). However, the expression of typical GABAergic hypothalamic neuronal markers such as POMC and NPY/AgRP (46), was unchanged between Prdm13 -/and Prdm13 +/+ mice (Supplemental Figure 2A), suggesting that PRDM13 is required for a specific subset of hypothalamic neurons.…”

REPRODUCTIVE TOXICOLOGY: Endocrine disruption and reproductive disorders: impacts on sexually dimorphic neuroendocrine pathways

“…Genistein and BPA exposure over only the first 48 h after birth is sufficient to alter other aspects of AVPV sexual differentiation including the number of dopaminergic neurons (Patisaul et al 2006). This finding is significant because GnRH neurons express dopamine receptors, and dopamine is a potent modulator of pre-and postsynaptic actions on GnRH neurons (Liu & Herbison 2013, Spergel 2019. Similarly, female mice perinatally exposed to BPA have an early vaginal opening (a marker of rodent puberty), lower circulating levels of LH, and significantly altered numbers of AVPV and ARC kisspeptin neurons (Ruiz-Pino et al 2019).…”