Dentate Granule Cell Network in Epilepsy

本课题涉及在齿状回中建立经常性兴奋回路的作用。 脑回在颞叶癫痫中起作用。颗粒细胞神经发生，颗粒细胞异常迁移， 苔藓纤维发芽形成一个混响网络，可以降低颗粒的阈值 细胞同步化，并潜在地降低齿状回对 癫痫的传播。匹罗卡品治疗的大鼠会变得癫痫，也会发展成 一致致密的颗粒细胞网络，将被用来研究特性和潜力 肺门异位颗粒细胞的病理生理作用。许多新的颗粒细胞作为一种 癫痫发作的结果会异常地迁移到齿状门部。大多数肺门异位颗粒细胞，不同于 正常或癫痫脑中的其他颗粒细胞、火动作电位和/或细胞爆发物 自发地处于静止膜电位。因此，这些细胞被假设为 促进颗粒细胞群在癫痫发作活动中的募集并增强兴奋性 CA3区。全细胞膜片钳记录将表征肝门异位颗粒的神经支配 并评估丰富的体周兴奋和稀疏的突触抑制的可能性 导致他们异常的兴奋性。我们还将确定自发的程度 放电/爆发可归因于T型钙电流增强，h电流表达减少 延迟整流钾电流和/或还原的BK和SK型钙依赖钾 电流。穿孔贴片记录将测试异常氯化物或钾 梯度在细胞过度兴奋中起作用。其他电生理学研究将评估 这些细胞的放电与内嗅觉皮质种群爆发的时间关系 神经元、正常分布的颗粒细胞或CAS锥体细胞以及这些细胞 接受来自CAS锥体细胞的反馈兴奋。 颞叶癫痫的药物治疗通常不能达到长期缓解。 该项目将阐明一种独特的解剖重组的病理生理作用 这种疾病，并可能发现新的治疗靶点。具体地说，这可能是有利的 高兴奋性在肺门异位颗粒细胞中的靶机制，但在正常情况下不是 颗粒细胞

This project concerns the role that establishment of recurrent excitatory circuitry in the dentate gyrus plays in temporal lobe epilepsy. Granule cell neurogenesis, aberrant granule cell migration, and mossy fiber sprouting create a reverberating network that can reduce the threshold for granule cell synchronization and potentially diminish the normally high resistance of the dentate gyrus to seizure propagation. Pilocarpine-treated rats, which become epileptic and also develop a consistently dense granule cell network, will be used to investigate the properties and potential pathophysiological role of hilar ectopic granule cells. Many of the new granule cells produced as a result of seizures migrate aberrantly into the dentate hilus. Most hilar ectopic granule cells, unlike other granule cells in either normal or epileptic brain, fire action potentials and/or cellular bursts spontaneously at resting membrane potential. Therefore these cells are hypothesized both to facilitate recruitment of the granule cell population into seizure activity and to enhance excitability in area CA3. Whole cell patch clamp recordings will characterize the innervation of hilar ectopic granule cells and assess the possibility that abundant perisomatic excitation and sparse synaptic inhibition contribute to their unusual excitability. We will also determine to what extent spontaneous firing/bursting can be attributed to enhanced T-type calcium current, expression of h current, reduced delayed rectifier potassium current and/or reduced BK- and SK-type calcium-dependent potassium current. Perforated patch recordings will test the possibility that an abnormal chloride or potassium gradient plays a role in cellular hyperexcitability. Additional electrophysiological studies will assess the temporal relationship between the firing of these cells and population bursts of entorhinal cortical neurons, normally-situated granule cells or CAS pyramidal cells and the possibility that these cells receive feedback excitation from CAS pyramidal cells. Pharmacotherapy of temporal lobe epilepsy usually fails to achieve long-term remission. This project will shed light on the pathophysiological role of an anatomical reorganization unique to this disorder and may uncover novel therapeutic targets. In particular, it may be advantageous to target mechanisms of hyperexcitability operative in hilar ectopic granule cells, but not in normal granule cells