AMINO-ACID NEUROTRANSMISSION AND INITIATION OF PUBERTY - EVIDENCE FROM NONKETOTIC HYPERGLYCINEMIA IN A FEMALE INFANT AND GONADOTROPIN-RELEASING-HORMONE SECRETION BY RAT HYPOTHALAMIC EXPLANTS

The pulse frequency of hypothalamic GnRH secretion increases at the on set of puberty. In rodents and primates, this process involves facilit atory and inhibitory effects mediated through hypothalamic N-methyl-D- aspartic acid (NMDA) and gamma-aminobutyric acid (GABA) receptors, res pectively. Precocious puberty was observed in an 11-month-old girl wit h nonketotic hyperglycinemia. This was thought to result from the effe ct of high concentrations of glycine (112 mu mol/L in cerebrospinal fl uid; normal, 3-12) acting on NMDA receptors as a coagonist of glutamat e. Regression of pubertal development during anticonvulsive treatment with GABA agonists (loreclezole and vigabatrin) suggested that the sti mulatory effects of glycine could be overcome by GABA receptor-mediate d inhibition. These two hypotheses were tested in the in vitro model o f the explanted hypothalamus from infantile (15-day-old) male rats. Gl ycine concentrations of 1-10 mu mol/L increased the pulse frequency of GnRH secretion. This acceleration was prevented by 7-chlorokynurenic acid, a glycine antagonist at the NMDA receptor complex, and by the GA BA agonist loreclezole. In addition, loreclezole and vigabatrin suppre ssed the developmental increase in the frequency of pulsatile GnRH sec retion. The observation of precocious puberty in an infant with hyperg lycinemia followed by pubertal regression during GABA agonist therapy and the in vitro findings in hypothalamic explants suggest that stimul atory inputs mediated through NMDA receptors and inhibitory inputs thr ough GABA receptors are involved in the initiation of puberty.