PT  - JOURNAL ARTICLE
AU  - Rachel Y. Cheong
AU  - Katja Czieselsky
AU  - Robert Porteous
AU  - Allan E. Herbison
TI  - Expression of ESR1 in Glutamatergic and GABAergic Neurons Is Essential for Normal Puberty Onset, Estrogen Feedback, and Fertility in Female Mice
AID  - 10.1523/JNEUROSCI.1776-15.2015
DP  - 2015 Oct 28
TA  - The Journal of Neuroscience
PG  - 14533--14543
VI  - 35
IP  - 43
4099  - http://www.jneurosci.org/content/35/43/14533.short
4100  - http://www.jneurosci.org/content/35/43/14533.full
SO  - J. Neurosci.2015 Oct 28; 35
AB  - 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 Esr1lox/lox line to generate animals with GABA-neuron-specific or glutamate-neuron-specific deletion of Esr1. Vgat-ires-Cre;Esr1lox/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;Esr1lox/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;Esr1lox/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.SIGNIFICANCE STATEMENT Circulating estradiol acts upon the brain to regulate the functioning of many neuronal networks, including those controlling reproduction. Acting in classic homeostatic negative or positive feedback modes, estradiol variably suppresses or enhances the activity of the gonadotropin-releasing hormone (GnRH) neurons throughout the ovarian cycle. We show here that estrogen receptor α (ESR1) within glutamate (VGLUT2) neurons is essential for both the negative and positive estradiol feedback loops. In contrast, ESR1 in GABA neurons is only required for estradiol positive feedback. These studies emphasize the importance of estradiol-modulated amino-acidergic neurons within the GnRH neuronal network and highlight an unexpected prominent role for ESR1-expressing glutamate neurons in fertility control.