Cholinergic control of GnRH neuron physiology and luteinizing hormone secretion in male mice: involvement of ACh/GABA co-transmission

Vastagh, Csaba and Farkas, Imre and Csillag, Veronika and Watanabe, Masahiko and Kalló, Imre and Liposits, Zsolt (2024) Cholinergic control of GnRH neuron physiology and luteinizing hormone secretion in male mice: involvement of ACh/GABA co-transmission. JOURNAL OF NEUROSCIENCE. ISSN 0270-6474

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Abstract

GnRH-synthesizing neurons orchestrate reproduction centrally. Early studies have proposed the contribution of acetylcholine (ACh) to hypothalamic control of reproduction, although the causal mechanisms haven't been clarified. Here, we report that in vivo pharmacogenetic activation of the cholinergic system increased the secretion of luteinizing hormone (LH) in orchidectomized mice. 3DISCO immunocytochemistry and electron microscopy revealed the innervation of GnRH neurons by cholinergic axons. Retrograde viral labeling initiated from GnRH-Cre neurons identified the medial septum and the diagonal band of Broca as exclusive sites of origin for cholinergic afferents of GnRH neurons. In acute brain slices, ACh and the ACh receptor (AChR) agonist carbachol evoked a biphasic effect on the firing rate in GnRH neurons, first increasing and then diminishing it. In the presence of tetrodotoxin, carbachol induced an inward current, followed by a decline in the frequency of mPSCs, indicating a direct influence on GnRH cells. RT-PCR and whole-cell patch-clamp studies revealed that GnRH neurons expressed both nicotinic (α4β2, α3β4, and α7) and muscarinic (M1-M5) ACh receptors. The nicotinic AChRs contributed to the nicotine-elicited inward current and the rise in firing rate. Muscarine via M1 and M3 receptors increased, while via M2 and M4 reduced the frequency of both miniature postsynaptic currents (mPSCs) and firing. Optogenetic activation of channelrhodopsin-2-tagged cholinergic axons modified GnRH neuronal activity and evoked co-transmission of ACh and GABA from a subpopulation of boutons. These findings confirm that the central cholinergic system immensely regulates GnRH neurons and activates the HPG-axis via ACh and ACh/GABA neurotransmissions in male mice.

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