Changes in hypothalamic gene expression associated with the arrest of pulsatile gonadotropin-releasing hormone release during infancy in the agonadalmale rhesus monkey (Macaca mulatta)

This study examined whether changes in the levels of the messenger RNAs (mR NAs) encoding the gamma-aminobutyric acid (GABA) synthesizing enzymes, glut amate decarboxylase (GAD)(65) and GAD(67) and transforming growth factor-al pha (TGF alpha) in the hypothalamus are correlated with the arrest of pulsa tile GnRH release during infancy in the agonadal male monkey. This experime nt also provided the opportunity to examine changes in hypothalamic GnRH ge ne expression during this critical phase of primate development. Male rhesu s monkeys were castrated at 1 week of age: four were killed 4-7 weeks after orchidectomy while pulsatile GnRH release was robust as reflected by high circulating LH levels, and four were killed at 12-15 months of age after es tablishing that pulsatile GnRH release had been arrested. GAD(65), GAD(67), TGF alpha, and GnRH mRNA levels were estimated using RNase protection assa ys employing homologous probes and the results were expressed relative to c yclophilin mRNA levels. GnRH peptide was measured by RIA. GAD(65) and GAD(6 7) mRNA levels in the hypothalamus of juveniles were significantly greater than those in neonatal monkeys. On the other hand, hypothalamic TGF alpha a nd GnRH mRNA (and peptide) levels in agonadal neonate and juvenile monkeys were indistinguishable. These results indicate that the molecular concomita nts associated with bringing the hypothalamic GnRH pulse generator into che ck in agonadal neonatal males are not a mirror image of those previously re ported at the time this neuronal network is reactivated at puberty when TGF alpha and GnRH gene expression increase and GAD(65) and GAD(67) mRNA level s remain unchanged. Thus, the neurobiological mechanism that reactivates pu lsatile GnRH release at puberty is likely to involve more than a simple rev ersal of that underlying inhibition of the same network in late infancy.