The Dopamine D4 Receptor Regulates Gonadotropin-Releasing Hormone Neuron Excitability in Male Mice.

Leigh Dairaghi,Susan Wray,David Shostak,Stephanie Constantin,Andrew Oh

doi:10.1523/eneuro.0461-21.2022

Abstract

Gonadotropin-releasing hormone (GnRH)-secreting neurons control fertility. The release of GnRH peptide regulates the synthesis and release of both luteinizing hormone (LH) and Follicle stimulation hormone (FSH) from the anterior pituitary. While it is known that dopamine regulates GnRH neurons, the specific dopamine receptor subtype(s) involved remain unclear. Previous studies in adult rodents have reported juxtaposition of fibers containing tyrosine hydroxylase (TH), a marker of catecholaminergic cells, onto GnRH neurons and that exogenous dopamine inhibits GnRH neurons postsynaptically through dopamine D1-like and/or D2-like receptors. Our microarray data from GnRH neurons revealed a high level of Drd4 transcripts [i.e., dopamine D4 receptor (D4R)]. Single-cell RT-PCR and immunocytochemistry confirmed GnRH cells express the Drd4 transcript and protein, respectively. Calcium imaging identified changes in GnRH neuronal activity during application of subtype-specific dopamine receptor agonists and antagonists when GABAergic and glutamatergic transmission was blocked. Dopamine, dopamine with D1/5R-specific or D2/3R-specific antagonists or D4R-specific agonists decreased the frequency of calcium oscillations. In contrast, D1/5R-specific agonists increased the frequency of calcium oscillations. The D4R-mediated inhibition was dependent on Gαi/o protein coupling, while the D1/5R-mediated excitation required Gαs protein coupling. Together, these results indicate that D4R plays an important role in the dopaminergic inhibition of GnRH neurons.

Highlights

Dopamine is a regulator of reproductive function at many levels along the hypothalamicpituitary-gonadal axis
The present results demonstrate that, while each gonadotropin-releasing hormone (GnRH) neuron did not express all five dopamine receptors, all dopamine receptors were present within the GnRH
All dopamine receptors are detected in prenatal GnRH neurons

Summary

Introduction

Dopamine is a regulator of reproductive function at many levels along the hypothalamicpituitary-gonadal axis. Tyrosine hydroxylase (TH)-containing fibers contact gonadotropin-releasing hormone (GnRH) neuron soma in the preoptic area and terminals in the median eminence (Jennes et al, 1983; Kuljis and Advis, 1989; Leranth et al., 1988). Both the tubero-infundibular dopaminergic pathway (Leranth et al, 1988; Mitchell et al., 2003) and the anteroventral periventricular nucleus (AVPV) (Horvath et al, 1993) contribute to the TH innervation of GnRH secreting neurons. The kisspeptin neuron subpopulation in the arcuate nucleus (ARC) acts on the tubero-infundibular dopaminergic pathway (Ribeiro et al., 2015) and the sexually dimorphic kisspeptin neuron subpopulation in the AVPV coexpresses TH (Clarkson and Herbison, 2011),(Simerly et al, 1985), indicating that dopamine may influence

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