NKCC1介导的新生大鼠缺氧缺血性脑损伤致惊厥的机制研究

围产期缺氧缺血导致的新生儿惊厥可引起癫痫、脑瘫等严重后遗症甚至威胁患儿生命，但发病原因复杂，机制不明。脑缺氧缺血能刺激成年动物齿状回(DG)神经前体细胞增殖并向损伤区域迁移,修复脑损伤。钠-钾-氯离子共转运体（NKCC1）是调节神经兴奋关键分子，最新研究证实早期热性惊厥可导致颗粒细胞滞留，提高成年期癫痫易感性，这种作用能被NKCC1抑制剂逆转。我们前期研究发现缺氧惊厥新生大鼠颗粒细胞（DGC）出现活跃的神经发生，膜离子通道功能抑制导致惊厥发作。新生儿缺氧缺血损伤后是否通过NKCC1介导的DGC滞留抑或远端迁移、异位增生，形成新惊厥病灶，影响成年癫痫易感性？本项目将追踪新生大鼠缺氧缺血损伤惊厥发生后，DGC的增生、迁移异位规律，并同时检测锥体细胞及DGC的NKCC1表达及功能，深入探讨缺氧缺血性脑损伤致惊厥的机制，为认识和完善围产期缺氧缺血导致的新生儿惊厥的发病机制提供依据。

Neonatal hypoxic-ischemic encephalopathy is a major cause of neonatal seizures, and can lead to epilepsy, mental retardation, cerebral palsy and other serious sequelae. Hypoxic-ischemic insult induces hippocampal pyramidal cell apoptosis but concurrently promotes neurogenesis in dentate gyrus, resulting in ectopic migration of granule cells. However, the intrinsic machanism is still unknown. It is also unknown whether the proliferation of newborn dentate gyrus granule cells are able to restore the function of CA1 pyramidal neurons. Sodium-potassium-chloride cotransporter (NKCC1), which is the key molecule regulating nervous excitement, showed distinct expression pattern and function in the neonatal brain and mature brain. Recent studies have shown that NKCC1 inhibitor partially recovered the dentate gyrus granul cells(DGC) ectopia and decreased the epilepsy susceptibility on neonatal rats with febrile seizures, suggesting a key role of NKCC1 in DGC ectopic migration. Our previous results showed that in hypoxia-induced convulsions neonatal brain, DGC presents active neurogenesis and membrane ion channels prohibited, suggesting hypoxia drive neurogenesis and ion channel is involoved in seizure. In the present proposal, we will investigate DGC proliferation, migration and ectopic pattern in hypoxic-ischemic brain injury rats and determine the expression and function of NKCC1 in in DGC and also on CA1 pyramidal neurons. Elucidating the signal pathways regulating hypoxic-ischemic brain injury may lead to the identification of new pharmacological targets for prevention and treatment of hypoxic-ischemic brain injury.