Lack of functional GABAB receptors disrupts normal Kiss1 mRNA expression in neonatal mice

DI GIORGIO N; CATALANO PN; GONALEZ B; BETTLER B; RULL SB; LIBERTUN C; LUX LANTOS V

Boston

Congreso; 93th Annual Meeting of The Endocrine Society; 2011

The Endocrine Society

Kisspeptin (Kiss1) is one of the most important neuropeptides in charge of the control of gonadotrophic axis controlling GnRH secretion. There are two populations of Kiss1 neurons; one is located in the antero-ventro periventricular nucleus (responsible for the estrogens-induced positive feedback) and the other one in the arcuate nucleus (responsible for the estrogens-induced negative feedback). Estrogens, produced by gonads or locally in the hypothalamus by p450 aromatase (p450aro), are key modulators in Kiss1 mRNA expression. We have previously shown that the absence of functional GABAB receptors (GABAB1KO) alters the hypothalamic-pituitary axis in adult mice (1) and more recently we have discovered that changes already occur in 4-day-old (PND4) mice. GABAB1KO mice have alterations in GnRH and glutamate decarboxilase-67 mRNAs expression in medial basal hypothalamus (MBH), but not in preoptic area-anterior hypothalamus (AH), and also in LH content and serum levels (2). However, these alterations differ from those observed in adulthood, suggesting additional regulations in later stages of development.  The aim of this study was to determine whether Kiss1 and p45aro were altered in PND4 GABAB1KO mice compared to WTs. Both sexes, wild-type (WT) and GABAB1KO mice were killed at PND4, their MBH and AH obtained to study Kiss1 and p450aro mRNA expression by RT-PCR and qRT-PCR respectively. Kiss1 expression depends on sex and genotype in MBH (two-way ANOVA: p<0.001). It was sexually dimorphic in WTs; its expression was higher in females than in males (p<0.01). However, this difference was lost in GABAB1KO mice. Moreover, Kiss1 mRNA decreased in GABAB1KO compared to WT females (p<0.001). In contrast, there were no differences between sexes or genotypes in Kiss1 mRNA expression in AH. P450aro mRNA expression was not different between groups either in MBH or in AH. These results show that, in agreement with previous results on GnRH expression, lack of functional GABAB receptors disrupts normal Kiss1 mRNA expression, specifically in the MBH, at an early postnatal stage of development. These alterations in Kiss1 expression are not accompanied by changes in aromatase expression.  Supported by grants from CONICET (PIP 363 2010); ANPCyT (BID PICT 2006 Nº00200 and BID PICT 2007 Nº 01050) and Universidad de Buenos Aires (ME 038). References    1.   Catalano PN, Di Giorgio N, Bonaventura MM, Bettler B, Libertun C, Lux-Lantos VA 2010 Lack of functional GABA(B) receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain. Am J Physiol Endocrinol Metab 298:E683-E696    2.   Di Giorgio N, Catalano PN, Bettler B, Libertun C, Lux-Lantos V, Alterations in the Regulation of the Gonadotrophic Axis In Neonatal GABAB1KO Mice. Abstract, Tenth International Symposium of GnRH, the Hypothalamic-Pituitary Axis in Cancer and Reproduction.Salzburg, Austria, February 6-8, 2011