Alterations in neural Kiss1 expression in adult GABAB1 receptor knockout mice.

NOELIA P DI GIORGIO; PAULA V LÓPEZ; SHEILA J SEMAAN; BERNHARD BETTLER; CARLOS LIBERTUN; VICTORIA A LUX-LANTOS; ALEXANDER S KAUFFMAN

Conferencia; Second World Conference on Kisspeptin Signaling in the Brain; 2012

Kisspeptin, encoded by Kiss1, stimulates GnRH neurons and is synthesized in the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei of the hypothalamus. Kiss1 is also expressed to a lesser extent in the medial amygdala (MeA) and bed nucleus of the stria terminalis (BNST), but the function of Kiss1 in these regions is unknown. The neurotransmitter GABA, acting through GABAA and GABAB receptors (GABABRs), also regulates reproduction. Adult female GABAB1R knockout (GABAB1RKO) mice have altered GnRH pulsatility and GnRH levels, as well as compromised fertility. However, the interaction between GABABRs and Kiss1 neurons is unknown. To test whether reproductive impairments in GABAB1RKOs reflect changes in kisspeptin, we first used double-label in situ hybridization (ISH) to assess GABAB1R co-localization in Kiss1 neurons. We found that all Kiss1 neurons (~98%) co-express GABAB1R in the AVPV. We next studied Kiss1 mRNA levels in the AVPV and ARC of adult wild-type (WT) and GABAB1RKO mice of both sexes. Kiss1 expression, assessed by ISH, was identical between genotypes in the AVPV and ARC. However, AVPV Kiss1 expression measured by qPCR was higher in GABAB1RKO females than WT females. Next, we analyzed Kiss1 levels in the BNST, MeA, and septum using ISH. Kiss1 levels were dramatically elevated in all 3 regions in GABAB1RKO mice of both sexes. Since sex steroids can strongly alter Kiss1 expression, we measured adult serum estradiol and testosterone levels via RIA. Interestingly, circulating sex steroid levels were equivalent between genotypes, suggesting alternate reasons for the high Kiss1 expression in extra-hypothalamic regions. Thus, GABAB1RKO mice have dramatic alterations in the neural Kiss1 system, particularly in the BNST and MeA. This abnormal Kiss1 expression may contribute to the observed alterations in the reproductive axis of GABAB1RKO mice. We are currently assessing whether this effect of GABABRs occurs directly in Kiss1 neurons, as well as the developmental ontogeny of the Kiss1 alterations.