Expression of ESR1 in Glutamatergic and GABAergic Neurons Is Essential for Normal Puberty Onset, Estrogen Feedback, and Fertility in Female Mice.
Circulating estradiol exerts a profound influence on the activity of the gonadotropin-releasing hormone (GnRH) neuronal network controlling fertility. Using genetic strategies enabling neuron-specific deletion of estrogen receptor α (Esr1), we examine here whether estradiol-modulated GABA and glutamate transmission are critical for the functioning of the GnRH neuron network in the female mouse. Using Vgat- and Vglut2-ires-Cre knock-in mice and ESR1 immunohistochemistry, we demonstrate that subpopulations of GABA and glutamate neurons throughout the limbic forebrain express ESR1, with ESR1-GABAergic neurons being more widespread and numerous than ESR1-glutamatergic neurons. We crossed Vgat- and Vglut2-ires-Cre mice with an Esr1(lox/lox) line to generate animals with GABA-neuron-specific or glutamate-neuron-specific deletion of Esr1. Vgat-ires-Cre;Esr1(lox/lox) mice were infertile, with abnormal estrous cycles, and exhibited a complete failure of the estrogen positive feedback mechanism responsible for the preovulatory GnRH surge. However, puberty onset and estrogen negative feedback were normal. Vglut2-ires-Cre;Esr1(lox/lox) mice were also infertile but displayed a wider range of deficits, including advanced puberty onset, abnormal negative feedback, and abolished positive feedback. Whereas <25% of preoptic kisspeptin neurons expressed Cre in Vgat- and Vglut2-ires-Cre lines, ∼70% of arcuate kisspeptin neurons were targeted in Vglut2-ires-Cre;Esr1(lox/lox) mice, possibly contributing to their advanced puberty phenotype. These observations show that, unexpectedly, ESR1-GABA neurons are only essential for the positive feedback mechanism. In contrast, we reveal the key importance of ESR1 in glutamatergic neurons for multiple estrogen feedback loops within the GnRH neuronal network required for fertility in the female mouse.
Centre for Neuroendocrinology and Department of Physiology, School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
Rachel Y
RY
Cheong
Centre for Neuroendocrinology and Department of Physiology, School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
Katja
K
Czieselsky
Centre for Neuroendocrinology and Department of Physiology, School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand.
Robert
R
Porteous
Centre for Neuroendocrinology and Department of Physiology, School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand allan.herbison@otago.ac.nz.
Allan E
http://orcid.org/0000-0002-9615-3022
AE
Herbison
D000818:Animals; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D004967:Estrogens / Q000502:physiology*; D030762:Estrous Cycle / Q000235:genetics / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology*; D005260:Female; D005298:Fertility / Q000235:genetics* / Q000502:physiology*; D005498:Follicular Phase / Q000235:genetics / Q000502:physiology; D055879:Gene Knock-In Techniques; D005971:Glutamates / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D059648:Kisspeptins / Q000378:metabolism / Q000502:physiology; D008032:Limbic System / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D016548:Prosencephalon / Q000378:metabolism; D012741:Sexual Maturation / Q000235:genetics* / Q000502:physiology*; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000502:physiology; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D047628:Estrogen Receptor alpha; D004967:Estrogens; D005971:Glutamates; D059648:Kisspeptins; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D007987:Gonadotropin-Releasing Hormone; D005680:gamma-Aminobutyric Acid
GABA; GnRH; estradiol; glutamate