Neuroendocrine developmental alterations in the gonadotropic axis in GABAB1KO mice.

PAOLO N. CATALANO, MARIA M. BONAVENTURA, BERNHARD BETTLER, CARLOS LIBERTUN AND VICTORIA LUX-LANTOS.

Toronto, Canada.

Congreso; 89th Annual Meeting of The Endocrine Society; 2007

The Endocrine Society

GABAB1 receptor subunit knock-out (GABAB1KO) female mice present alterations in cyclicity, fertility and an advanced post-castration LH rise (Catalano et al. Neuroendocrinology 82: 294, 2005). Here we determined the ontogenic content of hypothalamic GnRH in wild type (WT) and GABAB1KO male and females (4, 12, 20 day-old and adults) by RIA and the hypothalamic contents of GABA, glutamate and taurine in the same samples by HPLC. In adenohypophyseal cell cultures from adult male and female WT and GABAB1KO mice, basal and GnRH-induced LH and FSH release was determined by RIA. In WT males and females GnRH increased with age. Only on day 4 was WT GnRH content different from GABAB1KO in males [pg/mg tissue: WT: 12.0±1.2 vs. GABAB1KO: 6.5±0.9, p<0.01]. 4 day-old GABAB1KO females showed increased GnRH compared to age-matched WTs [pg/mg tissue: WT: 6.6±0.9 vs. GABAB1KO: 13.5±1.7, p<0.01], and similar to WT males. GnRH contents were lower in 20 day-old and adult GABAB1KO females than in WT controls. GABA increased along development in males without differences between genotypes. In WT females GABA increased reaching peak titers at 20 days and then decreased in adults. In contrast, GABA remained high in adult GABAB1KO females, similar to levels observed in males [nmoles/mg tissue: WT males: 9.4±0.4, GABAB1KO males: 9.9±0.4, WT females: 6.6±0.4, GABAB1KO females: 9.0±0.4, p<0.05]. The pattern of glutamate content was similar to GABA in both sexes and genotypes. Taurine decreased with age in both sexes without differences between genotypes. Pituitary cells secreted increased basal LH and FSH in GABAB1KO females compared to WT controls [LH, ng/50.000 cells: WT: 4.5±0.3 vs. GABAB1KO: 6.1±0.5, p<0.05]. No differences were observed in males. GnRH-induced LH release was reduced in GABAB1KO females [% increase: WT: 240.3±40.7 vs. GABAB1KO: 144.9±12.6, p<0.05], but not in males. GnRH-induced FSH secretion was diminished in GABAB1KO cells from both sexes.  We conclude that changes in the ontogeny of hypothalamic GnRH are observed in GABAB1KO mice. Alterations in neurotransmitters critically involved in GnRH secretion such as GABA and glutamate are also observed in GABAB1KO females. Finally, GABAB1KO mice pituitary cells show altered basal and GnRH-induced gonadotropin secretion. These results demonstrate that the absence of the expression of the GABAB1 subunit of the GABAB receptor markedly modifies de gonadotropin axis at several levels, particularly in females. Supported by grants from CONICET; ANPCyT (BID 1728/OC-AR PICT 2004 5-26307) and Universidad de Buenos Aires.