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J Neurosci. 2019 Jan 17. pii: 2880-18. doi: 10.1523/JNEUROSCI.2880-18.2019. [Epub ahead of print]

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

Author information

1
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109.
2
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801.
3
Division of Biological Sciences, University of Missouri, Columbia, MO, 65211.
4
Departments of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109.
5
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109 smoenter@umich.edu.
6
Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, 48109.
7
Internal Medicine, University of Michigan, Ann Arbor, MI, 48109.

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 if 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 if 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 GnRH neurons integrate fast-synaptic and intrinsic changes to increase firing rates during positive feedback.SIGNIFICANCE STATEMENTInfertility affects 15-20% of couples; failure to ovulate is a common cause. Understanding how the brain controls ovulation is critical for new developments in both infertility treatment and contraception. Ovarian estradiol alters both the intrinsic properties of GnRH neurons and synaptic inputs to these cells coincident with production of sustained GnRH release that ultimately triggers ovulation. We demonstrate here using dynamic clamp and mathematical modeling that estradiol-induced shifts in synaptic transmission alone can increase firing output, but that the intrinsic properties of GnRH neurons during positive feedback further poise these cells for increased response to higher frequency synaptic transmission. These data suggest that GnRH neurons integrate fast-synaptic and intrinsic changes to increase firing rates during the preovulatory GnRH surge.

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