Estrogen Protects Neurotransmission Transcriptome During Status Epilepticus

雌激素在癫痫持续状态期间保护神经传递转录组

Women with epilepsy commonly have premature onset of menopause. The decrease in estrogen levels is associated with increased occurrence of neurodegenerative processes and cognitive decline. Previously, we found that estradiol (E2) replacement in ovariectomized (OVX) female rats significantly reduced the seizure-related damage in the sensitive hilar region of hippocampal dentate gyrus (DG). However, the complex mechanisms by which E2 empowers the genomic fabrics of neurotransmission to resist damaging effects of status epilepticus (SE) are still unclear. We determined the protective effects of the estradiol replacement against kainic acid-induced SE-associated transcriptomic alterations in the DG of OVX rats. Without E2 replacement, SE altered expression of 44% of the DG genes. SE affected all major functional pathways, including apoptosis (61%), Alzheimer's disease (47%), cell cycle (59%), long-term potentiation (62%), and depression (55%), as well as synaptic vesicle cycle (62%), glutamatergic (53%), GABAergic (49%), cholinergic (52%), dopaminergic (55%), and serotonergic (49%) neurotransmission. However, in rats with E2 replacement the percentage of significantly affected genes after SE was reduced to the average 11% (from 8% for apoptosis to 32% for GABAergic synapse). Interestingly, while SE down-regulated most of the synaptic receptor genes in oil-injected females it had little effect on these receptors after E2-replacement. Our novel Pathway Protection analysis indicated that the E2-replacement prevented SE-related damage from 50% for GABA to 75% for dopaminergic transmission. The 15% synergistic expression between genes involved in estrogen signaling (ESG) and neurotransmission explains why low E2 levels result in down-regulation of neurotransmission. Interestingly, in animals with E2-replacement, SE switched 131 synergistically expressed ESG-neurotransmission gene pairs into antagonistically expressed gene pairs. Thus, the ESG pathway acts like a buffer against SE-induced alteration of neurotransmission that may contribute to the E2-mediated maintenance of brain function after the SE injury in postmenopausal women. We also show that the long-term potentiation is lost in OVX rats following SE but not in those with E2 replacement. The electrophysiological findings in OVX female rats with SE are corroborated by the high percentage of long-term potentiation regulated genes (62%) in oil-injected while only 13% of genes were regulated following SE in E2-replaced rats.

患有癫痫的妇女通常会过早绝经。雌激素水平的降低与神经退行性过程和认知下降的发生率增加有关。以前，我们发现雌二醇（E2）在卵巢切除（OVX）雌性大鼠中的替代能显著降低海马齿状回（DG）敏感门区的癫痫相关损伤。然而，E2使神经传递的基因组结构能够抵抗癫痫状态（SE）的损害作用的复杂机制仍不清楚。我们确定了雌二醇替代物对OVX大鼠DG中红藻氨酸诱导的SE相关转录组改变的保护作用。没有E2替代物，SE改变了44％的DG基因的表达。SE影响所有主要功能途径，包括细胞凋亡（61％），阿尔茨海默病（47％），细胞周期（59％），长期增强（62％）和抑郁（55％），以及突触囊泡循环（62％），谷氨酸能（53％），GABA能（49％），胆碱能（52％），多巴胺能（55％）和5-羟色胺能（49％）神经传递。然而，在E2替代的大鼠中，SE后显着受影响的基因的百分比降低至平均11％（从细胞凋亡的8％到GABA能突触的32％）。有趣的是，虽然SE下调了注射油的雌性大鼠的大多数突触受体基因，但它在E2替代后对这些受体几乎没有影响。我们的新型通路保护分析表明，E2替代可防止SE相关损伤从GABA的50％到多巴胺能传递的75％。参与雌激素信号传导（ESG）和神经传递的基因之间的15％协同表达解释了为什么低E2水平导致神经传递的下调。有趣的是，在E2替代的动物中，SE将131个协同表达的ESG神经传递基因对转化为拮抗表达的基因对。因此，ESG通路起到缓冲作用，对抗SE诱导的神经传递改变，这可能有助于绝经后妇女SE损伤后E2介导的脑功能维持。我们还表明，SE后OVX大鼠的长期增强作用消失，而E2替代者则没有。具有SE的OVX雌性大鼠的电生理学发现通过注射油中的高百分比的长期增强调节基因（62％）得到证实，而在E2替代的大鼠中仅有13％的基因在SE后受到调节。
2018 Jun 20 发表于Front Neurosci（IF3.648）

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Estrogen Protects Neurotransmission Transcriptome During Status Epilepticus

雌激素在癫痫持续状态期间保护神经传递转录组

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