Ebling F J, Cronin A S, Hastings M H
Department of Anatomy, University of Cambridge, UK.
Brain Res Bull. 1998 Dec;47(6):575-84. doi: 10.1016/s0361-9230(98)00139-7.
Although many studies provide evidence that glutamatergic pathways regulate the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, it is controversial as to whether they act directly upon GnRH neurons. The aim of the current study was to determine whether GnRH neurons are susceptible to the neurotoxic actions of specific glutamate agonists (N-methyl-D-aspartate [NMDA] and kainic acid), the rationale being that neurotoxic loss of GnRH neurons would provide evidence that the perikarya possess specific classes of glutamate receptor. Unilateral 1-microl injections of NMDA (12-120 mM), kainic acid (0.5-2.5 mM), or vehicle were stereotaxically directed at the preoptic area (mPOA)/diagonal band of Broca (dbB) in the region of the organum vasculosum of the lamina terminalis (OVLT) of male adult hamsters (Phodopus sungorus). The number and appearance of GnRH neurons were determined by immunocytochemistry 3-8 days later. The morphology of GnRH neurons in the vicinity of the injection sites appeared normal after both kainic acid and NMDA treatment, and there was no significant decrease in the numbers of GnRH perikarya identified following these treatments. Both agonists caused massive cellular loss when injected directly into cortical areas and striatum. In the experimental studies, there was little neuronal loss within the mPOA or dbB after either toxin, despite clear neuronal loss in areas adjacent to the injection sites, including ventral striatum and olfactory cortex. In follow-up studies, immunocytochemical and in situ hybridisation analysis of the NMDAR1 and NMDAR2 glutamate receptor subunits confirmed their widespread distribution in regions containing GnRH perikarya, but no colocalization within GnRH neurons was observed. The susceptibility of neural areas to NMDA neurotoxicity did not correlate with any difference in the regional expression of these glutamate receptor subunits. The resistance of GnRH neurons to the neurotoxic actions of two different glutamate agonists and the failure to detect colocalisation of NMDAR1 or NMDAR2 subunits within GnRH perikarya are consistent with the notion that the effects of glutamate upon GnRH secretion are not exerted directly upon GnRH cell bodies.
尽管许多研究提供了证据表明谷氨酸能通路调节下丘脑促性腺激素释放激素（GnRH）的分泌，但它们是否直接作用于GnRH神经元仍存在争议。本研究的目的是确定GnRH神经元是否易受特定谷氨酸激动剂（N-甲基-D-天冬氨酸[NMDA]和 kainic 酸）的神经毒性作用，其基本原理是GnRH神经元的神经毒性丧失将提供证据表明胞体具有特定类型的谷氨酸受体。将NMDA（12 - 120 mM）、kainic 酸（0.5 - 2.5 mM）或溶剂单侧1微升立体定位注射到成年雄性仓鼠（黑线毛足鼠）终板血管器（OVLT）区域的视前区（mPOA）/布罗卡斜带（dbB）。3 - 8天后通过免疫细胞化学确定GnRH神经元的数量和外观。在 kainic 酸和NMDA处理后，注射部位附近的GnRH神经元形态看起来正常，并且这些处理后鉴定出的GnRH胞体数量没有显著减少。当直接注射到皮质区域和纹状体时，两种激动剂都会导致大量细胞损失。在实验研究中，尽管注射部位相邻区域（包括腹侧纹状体和嗅觉皮质）有明显的神经元损失，但两种毒素注射后mPOA或dbB内几乎没有神经元损失。在后续研究中，对NMDAR1和NMDAR2谷氨酸受体亚基的免疫细胞化学和原位杂交分析证实它们在含有GnRH胞体的区域广泛分布，但未观察到在GnRH神经元内共定位。神经区域对NMDA神经毒性的敏感性与这些谷氨酸受体亚基的区域表达差异无关。GnRH神经元对两种不同谷氨酸激动剂的神经毒性作用具有抗性，并且未能在GnRH胞体内检测到NMDAR1或NMDAR2亚基的共定位，这与谷氨酸对GnRH分泌的作用不是直接作用于GnRH细胞体的观点一致。
