Definition of the estrogen negative feedback pathway controlling the GnRH pulse generator in female mice

H. James McQuillan, Jenny Clarkson, Alexia Kauff, Su Young Han, Siew Hoong Yip, Isaiah Cheong, Robert Porteous, Alison K. Heather and Allan E. Herbison ()
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H. James McQuillan: University of Otago School of Biomedical Sciences
Jenny Clarkson: University of Otago School of Biomedical Sciences
Alexia Kauff: University of Otago School of Biomedical Sciences
Su Young Han: University of Otago School of Biomedical Sciences
Siew Hoong Yip: University of Otago School of Biomedical Sciences
Isaiah Cheong: University of Otago School of Biomedical Sciences
Robert Porteous: University of Otago School of Biomedical Sciences
Alison K. Heather: University of Otago School of Biomedical Sciences
Allan E. Herbison: University of Otago School of Biomedical Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract The mechanisms underlying the homeostatic estrogen negative feedback pathway central to mammalian fertility have remained unresolved. Direct measurement of gonadotropin-releasing hormone (GnRH) pulse generator activity in freely behaving mice with GCaMP photometry demonstrated striking estradiol-dependent plasticity in the frequency, duration, amplitude, and profile of pulse generator synchronization events. Mice with Cre-dependent deletion of ESR1 from all kisspeptin neurons exhibited pulse generator activity identical to that of ovariectomized wild-type mice. An in vivo CRISPR-Cas9 approach was used to knockdown ESR1 expression selectively in arcuate nucleus (ARN) kisspeptin neurons. Mice with >80% deletion of ESR1 in ARN kisspeptin neurons exhibited the ovariectomized pattern of GnRH pulse generator activity and high frequency LH pulses but with very low amplitude due to reduced responsiveness of the pituitary. Together, these studies demonstrate that estrogen utilizes ESR1 in ARN kisspeptin neurons to achieve estrogen negative feedback of the GnRH pulse generator in mice.

Date: 2022
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DOI: 10.1038/s41467-022-35243-z

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