Estradiol Regulation of Kiss1 gene Expression in Extra-Hypothalamic Brain Regions of WT and GABAB receptor KO Mice.

STEPHENS SBZ; CHAHAL N; LUX LANTOS, V.; YANG J; BIZZOZZERO MARIANNE; KAUFFMAN AS; DI GIORGIO NP; PARRA RA; LIBERTUN, C

Orlando

Congreso; ENDO 2017; 2017

Estradiol regulation of Kiss1 gene expression in extra-hypothalamic brain regions of WT and GABABR KO miceNoelia P. Di Giorgio1*, Shannon B.Z. Stephens2*, Jennifer Yang2, Ruby A. Parra2, Navdeep Chahal2, Victoria A. Lux-Lantos1, Alexander S. Kauffman21Institute of Biology and Experimental Medicine?CONICET, Buenos Aires, Argentina2Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA*These authors contributed equally.Kisspeptin, encoded by the Kiss1 gene, stimulates GnRH release and is required for reproduction. Kiss1 neurons are predominantly located in the anteroventral periventricular (AVPV) and arcuate nuclei of the hypothalamus. However, Kiss1-expressing neurons are also found in extra-hypothalamic areas, such as the medial amygdala (MeA) and bed nucleus of the stria terminalis (BnST). Kiss1 expression in the MeA, as in the AVPV, is stimulated by estradiol (E2) acting via estrogen receptor α. In the absence of sex steroids, Kiss1 expression in the MeA falls to virtually undetectable levels. In addition to regulation by E2, our lab previously demonstrated that Kiss1 levels in the MeA, as well as in BnST and the lateral septum (LS), are significantly increased in gonad-intact GABABR KO mice versus WT mice. However, it is unknown if E2 exposure further increases MeA Kiss1 expression in GABABR KO mice, or if the absence of sex steroids in these KOs causes Kiss1 levels in these areas to decrease to the same near-absent levels as WT mice. To test this, male GABABR KO mice and WT littermates were gonadectomized (GDX) and received either no hormonal treatment or a Silastic E2 capsule for 1 week, after which brains were collected. Using in situ hybridization, we examined Kiss1 expression in extra-hypothalamic areas such as the MeA, BnST, and LS, as well as in the AVPV. As previously reported, within the AVPV, Kiss1 levels were similar between KO and WT mice of the same hormonal status. In contrast, GDX GABABR KO mice had notably greater Kiss1 expression in the MeA, BnST, and LS in comparison to GDX WT mice (which had virtually none), indicating that absent GABABR signaling upregulates Kiss1 levels even in the absence of sex steroids. In WT mice, E2 treatment increased Kiss1 expression in the MeA, BnST, and LS in comparison to GDX mice. Similarly, in GABABR KO mice, E2 treatment also increased Kiss1 expression in the MeA, BnST, and LS, with Kiss1 levels in these extra-hypothalamic regions tending to be several fold higher than in E2-treated WTs. Thus, both E2 and GABABR regulate Kiss1 in these extra-hypothalamic areas, whereas only E2 regulates hypothalamic Kiss1 levels. In summary, our data indicate that in the absence of sex steroids, ?baseline? extra-hypothalamic Kiss1 levels are significantly elevated if GABABR signaling is also absent, suggesting that Kiss1 in these areas, but not in the AVPV, is regulated by both E2 (stimulatory) and GABA (inhibitory). Further studies are needed to ascertain the function(s) of Kiss1 neurons located outside the hypothalamus.Research Support: NSF IOS-1025893 and IOS-1457226 (ASK); NIH T32 HD007203 (SBZS), NIH F32 HD088060 (SBZS), and P50 HD012303 (ASK).