Bourguignon J P, Gérard A, Purnelle G, Czajkowski V, Yamanaka C, Lemaître M, Rigo J M, Moonen G, Franchimont P
Department of Pediatrics, CHU Sart Tilman, University of Liège, Belgium.
J Neuroendocrinol. 1997 Mar;9(3):193-9. doi: 10.1046/j.1365-2826.1997.00568.x.
N-methyl-D-aspartate (NMDA) receptors and gamma-aminobutyric acid (GABA) receptors are involved in the mechanism of pulsatile gonadotrophin-releasing hormone (GnRH) secretion. The aim of this study was to elucidate the role of those receptors in the acceleration of pulsatile GnRH secretion seen at onset of puberty. Using hypothalamic explants from prepubertal (15 days), early pubertal (25 days) and adult (50 days) male rats, we studied the effects of pharmacological antagonists and antisense oligodeoxynucleotides on GnRH release evoked by NMDA and GABA receptor agonists as well as the interval between spontaneous GnRH secretory pulses. At the three studied ages, the muscimol-evoked release of GnRh is similarly inhibited by the GABAA receptor antagonist bicuculline. In contrast, the frequency of pulsatility is stimulated by bicuculline as indicated by a reduction of the mean GnRh interpulse interval from 60 to 40 min and such an effect is seen at 15 days only. The GnRH interpulse interval is also reduced by GABAA receptor antisense oligodeoxynucleotides at 15 days while no effects are seen at 25 days. At the three studied ages, the NMDA-evoked release of GnRH and the GnRh interpulse interval are similarly inhibited by 100 or 500 microM of the NMDA receptor antagonist 7-chlorokynurenic acid (7CK). These effects are consistent with the increase of GnRH interpulse interval caused by NR2A antisense oligodeoxynucleotides at 15 days (86 vs 64 min in controls) as well as 25 days (44 vs 36 min). A low (5 microM) concentration of 7CK does not result in any effect except a reduction of GnRH interpulse interval which is seen at 15 days only. A similar reduction of GnRh interpulse interval is obtained using NR2C antisense oligodeoxynucleotides at 15 days (50 vs 64 min in controls) while no effects are seen at 25 days (35 vs 36 min). At 25 days, muscimol can prevent the developmental increase in frequency of pulsatile GnRH secretion. In summary, pulsatile GnRH secretion by the prepubertal hypothalamus characteristically involves an inhibition mediated through GABAA receptors and the NR2C subunit of NMDA receptors. Based on these data, we propose a model for the mechanism of the onset of puberty which involves the disappearance or inactivation of GABAergic neurons located in the retrochiasmatic hypothalamus and expressing the NR2C subtype of NMDA receptors.
N-甲基-D-天冬氨酸（NMDA）受体和γ-氨基丁酸（GABA）受体参与了促性腺激素释放激素（GnRH）脉冲式分泌的机制。本研究的目的是阐明这些受体在青春期开始时所见到的GnRH脉冲式分泌加速过程中的作用。利用来自青春期前（15天）、青春期早期（25天）和成年（50天）雄性大鼠的下丘脑外植体，我们研究了药理学拮抗剂和反义寡脱氧核苷酸对NMDA和GABA受体激动剂诱发的GnRH释放以及自发性GnRH分泌脉冲间隔的影响。在三个研究年龄段，GABAA受体拮抗剂荷包牡丹碱同样抑制了蝇蕈醇诱发的GnRH释放。相反，荷包牡丹碱刺激了脉冲频率，表现为平均GnRH脉冲间隔从60分钟缩短至40分钟，且这种效应仅在15天时出现。GABAA受体反义寡脱氧核苷酸在15天时也缩短了GnRH脉冲间隔，而在25天时未见影响。在三个研究年龄段，100或500微摩尔的NMDA受体拮抗剂7-氯犬尿氨酸（7CK）同样抑制了NMDA诱发的GnRH释放和GnRH脉冲间隔。这些效应与15天（对照组为86分钟对64分钟）以及25天（44分钟对36分钟）时NR2A反义寡脱氧核苷酸导致的GnRH脉冲间隔增加一致。低浓度（5微摩尔）的7CK除了仅在15天时缩短GnRH脉冲间隔外未产生任何影响。在15天时使用NR2C反义寡脱氧核苷酸也得到了类似的GnRH脉冲间隔缩短（对照组为50分钟对64分钟），而在25天时未见影响（35分钟对36分钟）。在25天时，蝇蕈醇可以阻止GnRH脉冲式分泌频率的发育性增加。总之，青春期前下丘脑的GnRH脉冲式分泌特征性地涉及通过GABAA受体和NMDA受体的NR2C亚基介导的抑制作用。基于这些数据，我们提出了一个青春期开始机制的模型，该模型涉及位于视交叉后下丘脑且表达NMDA受体NR2C亚型的GABA能神经元的消失或失活。
