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

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