Changes in both neuron intrinsic properties and neurotransmission are needed to drive the increase in gnrh neuron firing rate during estradiol-positive feedback

Caroline Adams, R. Anthony Defazio, Catherine Christian, Lorin S. Milescu, Santiago Schnell, Suzanne M. Moenter

Research output: Contribution to journalArticle

Abstract

Central output of gonadotropin-releasing hormone (GnRH) neurons controls fertility and is sculpted by sex-steroid feedback. A switch of estradiol action from negative to positive feedback initiates a surge of GnRH release, culminating in ovulation. In ovariectomized mice bearing constant-release estradiol implants (OVX+E), GnRH neuron firing is suppressed in the morning (AM) by negative feedback and activated in the afternoon (PM) by positive feedback; no time-of-day-dependent changes occur in OVX mice. In this daily surge model, GnRH neuron intrinsic properties are shifted to favor increased firing during positive feedback. It is unclear whether this shift and the observed concomitant increase in GABAergic transmission, which typically excites GnRH neurons, are independently sufficient for increasing GnRH neuron firing rate during positive feedback or whether both are needed. To test this, we used dynamic clamp to inject selected previously recorded trains of GABAergic postsynaptic conductances (PSgs) collected during the different feedback states of the daily surge model into GnRH neurons from OVX, OVX+E AM, and OVX+E PM mice. PSg trains mimicking positive feedback initiated more action potentials in cells from OVX+E PM mice than negative feedback or OVX (open feedback loop) trains in all three animal models, but the positive-feedback train was most effective when applied to cells during positive feedback. In silico studies of model GnRH neurons in which >1000 PSg trains were tested exhibited the same results. These observations support the hypothesis that GnRHneurons integrate fast-synaptic and intrinsic changes to increase firing rates during positive feedback.

Original languageEnglish (US)
Pages (from-to)2091-2101
Number of pages11
JournalJournal of Neuroscience
Volume39
Issue number11
DOIs
StatePublished - Mar 13 2019

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Synaptic Transmission
Estradiol
Neurons
Gonadotropin-Releasing Hormone
Ovulation
Contraception
Computer Simulation
Action Potentials
Animal Models
Steroids

Keywords

  • Dynamic clamp
  • Estradiol feedback
  • GABA
  • GnRH

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Changes in both neuron intrinsic properties and neurotransmission are needed to drive the increase in gnrh neuron firing rate during estradiol-positive feedback. / Adams, Caroline; Anthony Defazio, R.; Christian, Catherine; Milescu, Lorin S.; Schnell, Santiago; Moenter, Suzanne M.

In: Journal of Neuroscience, Vol. 39, No. 11, 13.03.2019, p. 2091-2101.

Research output: Contribution to journalArticle

Adams, Caroline ; Anthony Defazio, R. ; Christian, Catherine ; Milescu, Lorin S. ; Schnell, Santiago ; Moenter, Suzanne M. / Changes in both neuron intrinsic properties and neurotransmission are needed to drive the increase in gnrh neuron firing rate during estradiol-positive feedback. In: Journal of Neuroscience. 2019 ; Vol. 39, No. 11. pp. 2091-2101.
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abstract = "Central output of gonadotropin-releasing hormone (GnRH) neurons controls fertility and is sculpted by sex-steroid feedback. A switch of estradiol action from negative to positive feedback initiates a surge of GnRH release, culminating in ovulation. In ovariectomized mice bearing constant-release estradiol implants (OVX+E), GnRH neuron firing is suppressed in the morning (AM) by negative feedback and activated in the afternoon (PM) by positive feedback; no time-of-day-dependent changes occur in OVX mice. In this daily surge model, GnRH neuron intrinsic properties are shifted to favor increased firing during positive feedback. It is unclear whether this shift and the observed concomitant increase in GABAergic transmission, which typically excites GnRH neurons, are independently sufficient for increasing GnRH neuron firing rate during positive feedback or whether both are needed. To test this, we used dynamic clamp to inject selected previously recorded trains of GABAergic postsynaptic conductances (PSgs) collected during the different feedback states of the daily surge model into GnRH neurons from OVX, OVX+E AM, and OVX+E PM mice. PSg trains mimicking positive feedback initiated more action potentials in cells from OVX+E PM mice than negative feedback or OVX (open feedback loop) trains in all three animal models, but the positive-feedback train was most effective when applied to cells during positive feedback. In silico studies of model GnRH neurons in which >1000 PSg trains were tested exhibited the same results. These observations support the hypothesis that GnRHneurons integrate fast-synaptic and intrinsic changes to increase firing rates during positive feedback.",
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