AU  - Wang, Luhong
AU  - Burger, Laura L.
AU  - Greenwald-Yarnell, Megan L.
AU  - Myers, Martin G.
AU  - Moenter, Suzanne M.
TI  - Glutamatergic transmission to hypothalamic kisspeptin neurons is differentially regulated by estradiol through estrogen receptor α in adult female mice.
PT  - JOURNAL ARTICLE
DP  - 2017 Nov 07 
TA  - The Journal of Neuroscience 
4099 - http://www.jneurosci.org/content/early/2017/11/07/JNEUROSCI.2428-17.2017.abstract 
SO - J. Neurosci. 2017 Nov 07; 
AID  - 10.1523/JNEUROSCI.2428-17.2017 [doi] 
AB  - Estradiol feedback regulates gonadotropin-releasing hormone (GnRH) neurons and subsequent luteinizing hormone (LH) release. Estradiol acts through estrogen receptor α (ERα)-expressing afferents of GnRH neurons including kisspeptin neurons in the anteroventral periventricular (AVPV) and arcuate nuclei, providing homeostatic feedback on episodic GnRH/LH release as well as positive feedback to control ovulation. Ionotropic glutamate receptors are important for estradiol feedback but it is not known where they fit in the circuitry. Estradiol negative feedback decreased glutamatergic transmission to AVPV and increased it to arcuate kisspeptin neurons; positive feedback had the opposite effect. Deletion of ERα in kisspeptin cells decreased glutamate transmission to AVPV neurons and markedly increased it to arcuate kisspeptin neurons, which also exhibited increased spontaneous firing rate. KERKO mice had increased LH pulse frequency, indicating loss of negative feedback. These observations indicate ERα in kisspeptin cells is required for appropriate differential regulation of these neurons and neuroendocrine output by estradiol.SIGNIFICANCE STATEMENTThe brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Ovarian estradiol regulates the pattern of GnRH (negative feedback) and initiate a surge of release that triggers ovulation (positive feedback). GnRH neurons do not express the estrogen receptor needed for feedback (ERα); kisspeptin neurons in the arcuate and anteroventral periventricular nuclei are postulated to mediate negative and positive feedback, respectively. Here we extend the network through which feedback is mediated by demonstrating that glutamatergic transmission to these kisspeptin populations is differentially regulated during the reproductive cycle and by estradiol. Electrophysiological and in vivo hormone profile experiments on kisspeptin-specific ERα knockout mice demonstrate ERα in kisspeptin cells is required for appropriate differential regulation of these neurons and for neuroendocrine output.