Iacobas Dumitru A, Iacobas Sanda, Nebieridze Nino, Velíšek Libor, Velíšková Jana
Center for Computational Systems Biology, Prairie View A&M University, Prairie View, TX, United States.
DP Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, United States.
Front Neurosci. 2018 Jun 20;12:332. doi: 10.3389/fnins.2018.00332. eCollection 2018.
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.
癫痫女性通常会过早进入更年期。雌激素水平的降低与神经退行性变过程的发生率增加和认知能力下降有关。此前，我们发现给去卵巢（OVX）雌性大鼠补充雌二醇（E2）可显著减少海马齿状回（DG）敏感的门区与癫痫发作相关的损伤。然而，E2增强神经传递的基因组结构以抵抗癫痫持续状态（SE）损伤作用的复杂机制仍不清楚。我们确定了雌二醇替代对OVX大鼠DG中 kainic 酸诱导的SE相关转录组改变的保护作用。在不补充E2的情况下，SE改变了DG中44%的基因表达。SE影响了所有主要的功能途径，包括细胞凋亡（61%）、阿尔茨海默病（47%）、细胞周期（59%）、长时程增强（62%）和抑郁症（55%），以及突触小泡循环（62%）、谷氨酸能（53%）、γ-氨基丁酸能（49%）、胆碱能（52%）、多巴胺能（55%）和5-羟色胺能（49%）神经传递。然而，在补充E2的大鼠中，SE后受显著影响的基因百分比降至平均11%（从细胞凋亡的8%到γ-氨基丁酸能突触的32%）。有趣的是，虽然SE下调了注射油的雌性大鼠中的大多数突触受体基因，但在补充E2后对这些受体几乎没有影响。我们新颖的通路保护分析表明，E2替代可防止SE相关损伤，从γ-氨基丁酸的50%到多巴胺能传递的75%。雌激素信号传导（ESG）相关基因与神经传递相关基因之间15%的协同表达解释了为什么低E2水平会导致神经传递下调。有趣的是，在补充E2的动物中，SE将131个协同表达的ESG-神经传递基因对转换为拮抗表达的基因对。因此，ESG通路就像一个缓冲器，可防止SE诱导的神经传递改变，这可能有助于绝经后女性SE损伤后脑功能的E2介导维持。我们还表明，OVX大鼠在SE后长时程增强消失，但在补充E2的大鼠中则没有。在注射油的OVX雌性大鼠中，SE后长时程增强调节基因的高百分比（62%）证实了电生理结果，而在补充E2的大鼠中，SE后只有13%的基因受到调节。
