Estradiol increases glutamate and gaba neurotransmission into gnrh neurons via retrograde no-signaling in proestrous mice during the positive estradiol feedback period

Imre Farkas, Flóra Bálint, Erzsébet Farkas, Csaba Vastagh, Csaba Fekete, Zsolt Liposits

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Surge release of gonadotropin-releasing hormone (GnRH) is essential in the activation of pituitary gonadal unit at proestrus afternoon preceded by the rise of serum 17β-estradiol (E2) level during positive feedback period. Here, we describe a mechanism of positive estradiol feedback regulation acting directly on GnRH-green fluorescent protein (GFP) neurons of mice. Whole-cell clamp and loose patch recordings revealed that a high physiological dose of estradiol (200 pM), significantly increased firing rate at proestrus afternoon. The mPSC frequency at proestrus afternoon also increased, whereas it decreased at metestrus afternoon and had no effect at proestrus morning. Inhibition of the estrogen receptor β (ERβ), intracellular blockade of the Src kinase and phosphatidylinositol 3 kinase (PI3K) and scavenge of nitric oxide (NO) inside GnRH neurons prevented the facilitatory estradiol effect indicating involvement of the ERβ/Src/PI3K/Akt/nNOS pathway in this fast, direct stimulatory effect. Immunohistochemistry localized soluble guanylate cyclase, the main NO receptor, in both glutamatergic and GABAergic terminals innervating GnRH neurons. Accordingly, estradiol facilitated neurotransmissions to GnRH neurons via both GABAA-R and glutamate/AMPA/kainate-R. These results indicate that estradiol acts directly on GnRH neurons via the Eβ/Akt/nNOS pathway at proestrus afternoon generating NO that retrogradely accelerates GABA and glutamate release from the presynaptic terminals contacting GnRH neurons. The newly explored mechanism might contribute to the regulation of the GnRH surge, a fundamental prerequisite of the ovulation.

Original languageEnglish
Article numbere0057-18.2018
JournaleNeuro
Volume5
Issue number4
DOIs
Publication statusPublished - Jul 1 2018

Keywords

  • GABA
  • Glutamate
  • GnRH neuron
  • Positive estradiol feedback
  • Retrograde nitric oxide signalling
  • Slice electrophysiology

ASJC Scopus subject areas

  • Neuroscience(all)

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