GABAB Receptor Antagonism from Birth to Weaning Permanently Modifies <b><i>Kiss1</i></b> Expression in the Hypothalamus and Gonads in Mice

Abstract

Introduction: The kisspeptin gene Kiss1 is expressed in two hypothalamic areas: anteroventral periventricular nucleus/periventricular nucleus (AVPV/PeN) and arcuate nucleus (ARC), and also in gonads. Evidences suggest that gamma-amino butyric acid B receptors (GABAB) signaling can regulate Kiss1 expression. Here we inhibited GABAB signaling from PND2-PND21 and evaluated the hypothalamic-pituitary-gonadal (HPG) axis. Methods: BALB/c mice were treated on postnatal days 2-21 (PND2-PND21) with CGP55845 (GABAB antagonist), and evaluated in PND21 and adulthood: gene expression (qPCR) in hypothalamus and gonads, hormones by radioimmunoassay, gonad histochemistry (H&amp;E), puberty onset, estrous cycles. Results: At PND21, CGP inhibited Kiss1 and Tac2 and increased Pdyn and Gabbr1 in the ARC of both sexes and decreased Th only in female AVPV/PeN. Serum follicle-stimulating hormone (FSH) and testis weight decreased in CGP-males and puberty onset was delayed. In adults, Kiss1, Tac2, Pdyn, Pgr, Cyp19a1, Gad1 were downregulated, while Gabbr1 was upregulated in the ARC of both sexes. In the AVPV/PeN, Kiss1, Th, Cyp19a1 and Pgr decreased while Gad1 increased in CGP-females, whereas Cyp19a1 increased in CGP-males. Serum FSH increased in CGP-males while prolactin increased in CGP-females. Testosterone and progesterone increased in ovaries from CGP-females, in which Kiss1, Cyp19a1 and Esr1 were downregulated while Hsd3b2 was upregulated, together with increased atretic and decreased ovulatory follicles. Testes from CGP-males showed decreased progesterone, increased Gabbr1, Kiss1, Kiss1r, Esr2 and decreased Cyp19a1 and clear signs of seminiferous tubules atrophy. Conclusion: These results demonstrate that appropriate GABAB signaling during this critical prepubertal period is necessary for the normal development of the HPG axis.

Sexual Dimorphism in Kisspeptin Signaling

“…Moreover, gamma-amino butyric acid B (GABAB) receptor signaling can regulate Kiss1 expression in both sexes [ 86 ]. Inhibition of GABAB signaling with a selective antagonist (CGP) reduced the expression of Kiss1 and Tac2 (neurokinin B) genes in the ARC nucleus [ 86 ].…”

“…Moreover, gamma-amino butyric acid B (GABAB) receptor signaling can regulate Kiss1 expression in both sexes [ 86 ]. Inhibition of GABAB signaling with a selective antagonist (CGP) reduced the expression of Kiss1 and Tac2 (neurokinin B) genes in the ARC nucleus [ 86 ]. CGP-treatment resulted in decreased FSH level and delayed the onset of puberty in male mice, whereas increased the number of atretic and decreased the number of ovulatory follicles in females [ 86 ].…”

“…Inhibition of GABAB signaling with a selective antagonist (CGP) reduced the expression of Kiss1 and Tac2 (neurokinin B) genes in the ARC nucleus [ 86 ]. CGP-treatment resulted in decreased FSH level and delayed the onset of puberty in male mice, whereas increased the number of atretic and decreased the number of ovulatory follicles in females [ 86 ]. Studies also suggest the importance of epigenetic mechanisms regulating hypothalamic KP expression [ 87 ].…”