High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons.

Jian Qiu,Chunguang Zhang,Stephanie L Padilla,Richard D Palmiter,Oline K Rønnekleiv,Martin J Kelly,Casey C Nestor

doi:10.7554/elife.16246

Jian Qiu, Chunguang Zhang + Show 5 more

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https://doi.org/10.7554/elife.16246

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Abstract

Kisspeptin (Kiss1) and neurokinin B (NKB) neurocircuits are essential for pubertal development and fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (Kiss1(ARH)) co-express Kiss1, NKB, dynorphin and glutamate and are postulated to provide an episodic, excitatory drive to gonadotropin-releasing hormone 1 (GnRH) neurons, the synaptic mechanisms of which are unknown. We characterized the cellular basis for synchronized Kiss1(ARH) neuronal activity using optogenetics, whole-cell electrophysiology, molecular pharmacology and single cell RT-PCR in mice. High-frequency photostimulation of Kiss1(ARH) neurons evoked local release of excitatory (NKB) and inhibitory (dynorphin) neuropeptides, which were found to synchronize the Kiss1(ARH) neuronal firing. The light-evoked synchronous activity caused robust excitation of GnRH neurons by a synaptic mechanism that also involved glutamatergic input to preoptic Kiss1 neurons from Kiss1(ARH) neurons. We propose that Kiss1(ARH) neurons play a dual role of driving episodic secretion of GnRH through the differential release of peptide and amino acid neurotransmitters to coordinate reproductive function.

Highlights

Pulsatile secretion of gonadotropin-releasing hormone 1 (GnRH), and pulsatile release of pituitary luteinizing hormone (LH), is required for normal reproductive function, and there is increasing evidence that kisspeptin (Kiss1) neurons in the hypothalamic arcuate nucleus (ARH) are a component of the “GnRH pulse generator” (Navarro et al, 2009; Navarro et al, 2011a; Lehman et al, 2010a; Okamura et al, 2013)
To determine whether the slow excitatory postsynaptic potential (EPSP) is a unique property of Kiss1ARH neurons, we tested the anteroventral periventricular nucleus (AVPV)/preoptic nucleus (PeN) population of Kiss1ARH neurons project to AVPV/PeN (Kiss1) neurons with 10-s stimulation at 20 Hz (Figure 2I); these neurons had a transient hyperpolarization after stimulation and a return to continuous firing ~30 s after the stimulation
Given that the expression of Kiss1, dynorphin, neurokinin B (NKB) and tachykinin receptor 3 (Tacr3) are all down-regulated in kisspeptin neurons by E2treatment (Smith et al, 2005; Gottsch et al, 2009; Navarro et al, 2011a; Ruiz-Pino et al, 2012), we asked the question whether the slow EPSP would be reduced by E2 or even vary during the ovulatory cycle

Summary

Introduction

Pulsatile secretion of gonadotropin-releasing hormone 1 (GnRH), and pulsatile release of pituitary luteinizing hormone (LH), is required for normal reproductive function, and there is increasing evidence that kisspeptin (Kiss1) neurons in the hypothalamic arcuate nucleus (ARH) are a component of the “GnRH pulse generator” (Navarro et al, 2009; Navarro et al, 2011a; Lehman et al, 2010a; Okamura et al, 2013). The “GnRH pulse generator” consists of bursts of multiunit activity (MUA) in the arcuate nucleus that are timed with pulses of LH secretion, and this phenomenon has been demonstrated in the monkey (Knobil, 1989), goat (Wakabayashi et al, 2010; Okamura et al, 2013), and rat (Kimura et al, 1991; KinseyJones et al, 2008). Two major populations of kisspeptin-synthesizing neurons exist one in the anterior preoptic area and the other in the ARH (Lehman et al, 2010b).

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