Promotive effect of neurosteroids on memory- and emotion-related neuronal communication in the hippocampus

神经类固醇在大脑中从头产生，通过剧烈调节海马神经元中神经递质受体的离子电导率来调节学习和记忆过程。神经甾体形成的途径和神经元信号传递的调控模式尚未得到很好的阐明。本研究发现，由细胞色素P450scc、羟类固醇磺酸转移酶、类固醇急性调节蛋白（StAR）、3 β -羟类固醇脱氢酶、P450c17和P450arom组成的神经甾体生成系统存在于大鼠海马锥体神经元和颗粒神经元中。这表明海马体中神经类固醇的主要来源不是神经胶质细胞，而是神经元。此外，我们发现，通过高效液相色谱分析和放射免疫测定，胆固醇通过前体类固醇、孕烯醇酮、脱氢表雄酮和雄酮被积极代谢为17 -雌二醇（E2）。我们还发现，更多的神经甾体生成速率是通过线粒体StAR加工调节的，这是由Ca^<2+>通过NMDA受体流入急性诱导的。P450c17酶及其活性（DHEA合成）首次在哺乳动物大脑中得到证实，由此我们现在可以将下游类固醇，如E2和睾酮，视为“真正的”神经类固醇。我们还研究了神经类固醇对海马神经元信号传递的急性影响。在4周龄雄性Wistar大鼠海马片中，观察到孕烯醇酮（500 nM）可非常剧烈地（在1秒内）增强Ca^<2+>通过NMDA受体的内流，导致诱发LTP所需的破伤风刺激强度（从100 Hz， 1秒到30 Hz， 0.5秒）降低。在海马神经元一氧化氮的生产也急剧促进应用孕烯醇酮硫酸。短时间E2 （1-100 nM, 20 min）以剂量依赖的方式抑制4周龄雄性Wistar大鼠海马片LTP的形成，并刺激破伤风（100 Hz, 1 sec）。另一方面，同样的E2处理增强了10周龄雄性大鼠海马切片中的LTP。这些结果表明，E2对神经元信号传递的作用模式取决于获得海马切片的动物的年龄。皮质酮，一种最有效的应激类固醇，抑制LTP诱导和Ca^<2+>通过海马片NMDA受体内流。这一结果可能为急性强应激所致创伤后应激障碍提供细胞生理学依据。少

Neurosteroids, produced de novo in the brain, regulate learning and memory processes by acutely modulating the ion conductivity of neurotransmitter receptors in hippocampal neurons. The pathway of neurosteroidogenesis and the regulation mode of neuronal signal transmission have not been well-elucidated. In the present study, we have discovered that a neurosteroidogenic system, composed of cytochrome P450scc, hydroxysteroid sulfotransferase, steroidogenic acute regulatory protein (StAR), 3beta-hydroxysteroid dehydrogenase, P450c17 and P450arom, localizes in pyramidal neurons and granule neurons in the rat hippocampus. This indicates that the main source of neurosteroids in the hippocampus is not glial cells, as has been believed, but neurons. Furthermore, we have found, with HPLC analysis and radioimmunoassay, that cholesterol is actively metabolized to 17beta-estradiol (E2) through precursor steroids, pregnenolone, dehydroepiandrosterone (DHEA) and androsterone. We have also found that … More the rate of neurosteroidogenesis was regulated through mitochondrial StAR processing, which was acutely induced by Ca^<2+> influx via NMDA receptors. P450c17 enzyme and its activity (DHEA synthesis) were demonstrated for the first time in the mammalian brain, by which we can now regard downstream steroids, such as E2 and teststerone, as 'true' neurosteroids.We also examined the acute effect of neurosteroids on the signal transmission of hippocampal neurons. Pregnenolone sulfate (500 nM) was observed to potentiate Ca^<2+> influx via NMDA receptors very acutely (within 1 sec), which resulted in the reduction in the strength of tetanus stimulation required to induce LTP (from 100 Hz, 1 sec to 30 Hz, 0.5 sec) in hippocampal slices prepared from 4-week-old male Wistar rats. Nitric oxide production in hippocampal neurons was also acutely promoted by the application with pregnenolone sulfate. A short time treatment with E2 (1-100 nM, 20 min) suppressed LTP formation, in dose-dependent manner, in hippocampal slices obtained from 4-week-old male Wistar rats and stimulated with tetanus stimulation (100 Hz, 1 sec). On the other hand, the same E2 treatment potentiated LTP in hippocampal slices prepared from 10-week-old male rats. These results suggest that the mode of E2 action on neuronal signal transmission varies depending on the age of animals from which hippocampal slices were obtained. Corticosterone, a most potent stress steroid, suppressed LTP induction and Ca^<2+> influx via NMDA receptors in hippocampal slices. This result might give the cell physiological basis for PTSD induced by the acute and strong stress. Less