Heger Sabine, Seney Marianne, Bless Elizabeth, Schwarting Gerald A, Bilger Marie, Mungenast Alison, Ojeda Sergio R, Tobet Stuart A
Division of Neuroscience, Oregon National Regional Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA.
Endocrinology. 2003 Jun;144(6):2566-79. doi: 10.1210/en.2002-221107.
gamma-Aminobutyric acid (GABA) inhibits the embryonic migration of GnRH neurons and regulates hypothalamic GnRH release. A subset of GnRH neurons expresses GABA along their migratory route in the nasal compartment before entering the brain, suggesting that GABA produced by GnRH neurons may help regulate the migratory process. To examine this hypothesis and the possibility that persistence of GABA production by GnRH neurons may affect subsequent reproductive function, we generated transgenic mice in which the expression of glutamic acid decarboxylase-67 (GAD-67), a key enzyme in GABA synthesis, is targeted to GnRH neurons under the control of the GnRH gene promoter. On embryonic d 15, when GnRH neurons are still migrating, the transgenic animals had more GnRH neurons in aberrant locations in the cerebral cortex and fewer neurons reaching the hypothalamic-preoptic region, whereas migration into the brain was not affected. Hypothalamic GnRH content in mutant mice was low during the first week of postnatal life, increasing to normal values during infantile development (second week after birth) in the presence of increased pulsatile GnRH release. Consistent with these changes, serum LH and FSH levels were also elevated. Gonadotropin release returned to normal values by the time steroid negative feedback became established (fourth week of life). Ovariectomy at this time demonstrated an enhanced gonadotropin response in transgenic animals. Although the onset of puberty, as assessed by the age at vaginal opening and first ovulation, was not affected in the mutant mice, estrous cyclicity and adult reproductive capacity were disrupted. Mutant mice had reduced litter sizes, increased time intervals between deliveries of litters, and a shorter reproductive life span. Thus, GABA produced within GnRH neurons does not delay GnRH neuronal migration, but instead serves as a developmental cue that increases the positional diversity of these neurons within the basal forebrain. In addition, the results suggest that the timely termination of GABA production within the GnRH neuronal network is a prerequisite for normal reproductive function. The possibility arises that similar abnormalities in GABA homeostasis may contribute to syndromes of hypothalamic amenorrhea/oligomenorrhea in humans.
γ-氨基丁酸（GABA）抑制促性腺激素释放激素（GnRH）神经元的胚胎迁移，并调节下丘脑GnRH的释放。一部分GnRH神经元在进入大脑之前，在鼻腔区域的迁移路径上表达GABA，这表明GnRH神经元产生的GABA可能有助于调节迁移过程。为了验证这一假设以及GnRH神经元持续产生GABA可能影响后续生殖功能的可能性，我们构建了转基因小鼠，其中在GnRH基因启动子的控制下，将GABA合成中的关键酶谷氨酸脱羧酶-67（GAD-67）的表达靶向到GnRH神经元。在胚胎第15天，当GnRH神经元仍在迁移时，转基因动物在大脑皮层异常位置有更多的GnRH神经元，而到达下丘脑视前区的神经元较少，而进入大脑的迁移不受影响。突变小鼠出生后第一周下丘脑GnRH含量较低，在婴儿期发育（出生后第二周）期间，随着GnRH脉冲式释放增加，GnRH含量增加至正常水平。与这些变化一致，血清促黄体生成素（LH）和促卵泡生成素（FSH）水平也升高。到类固醇负反馈建立时（出生后第四周），促性腺激素释放恢复到正常水平。此时进行卵巢切除术显示转基因动物的促性腺激素反应增强。尽管通过阴道开口年龄和首次排卵年龄评估的青春期开始时间在突变小鼠中未受影响，但发情周期和成年生殖能力受到破坏。突变小鼠的窝仔数减少，产仔间隔时间增加，生殖寿命缩短。因此，GnRH神经元内产生的GABA不会延迟GnRH神经元的迁移，而是作为一种发育信号，增加这些神经元在前脑基部的位置多样性。此外，结果表明，GnRH神经元网络内GABA产生的及时终止是正常生殖功能的先决条件。由此产生一种可能性，即GABA稳态的类似异常可能导致人类下丘脑闭经/月经过少综合征。
