Vesicular Zinc of Recurrent Mossy Fiber in Epilepsy

描述（由申请人提供）：癫痫是一种慢性神经系统疾病，影响美国约1%的人口。虽然它通常可以用药物治疗，但约25 - 30%的癫痫患者继续经历反复发作，尽管有多种药物治疗。齿状回（DG）通常起过滤器的作用。它可以阻止同步活动传播到易患癫痫的海马体。DG的这种过滤器或“看门人”属性在颞叶癫痫（TLE）中受到损害。在TLE中，颗粒细胞的轴突苔藓纤维（MF）经常发芽并异常支配DG的体细胞层和内部分子层。复发性MF介导的混响兴奋，可以降低颗粒细胞同步化的阈值，并可能促进参与癫痫发作的DG。已知复发性MF与颞叶癫痫密切相关，但对其了解甚少。MF的独特性质是它们含有高浓度的锌（Zn2+），其共定位于突触囊泡中并与谷氨酸共同释放。Zn~（2+）对多种离子通道有调节作用，包括抑制NMDA和GABA受体门控通道电流。在这项研究中，匹鲁卡品治疗的大鼠，成为癫痫和发展一个一致的密集复发MF途径将被用来调查和表征锌释放从复发MF，这是很少的信息。我们还将确定MF释放的Zn~（2+）转运到颗粒细胞。建议的实验是基于我们以前发表的数据和初步研究，这导致需要完成这些建议的高度可行的实验。本研究结果为进一步研究锌离子释放对神经传递的影响以及复发性MF在TLE发病中的作用奠定了基础。研究结果将有助于制定更合理、更明智或更有针对性的癫痫治疗策略。

DESCRIPTION (provided by applicant): Epilepsy is a chronic neurological condition that affects about 1% of the population in the United States. Although it is usually treatable with medications, about 25-30% of epileptic patients continue to experience recurrent seizure in spite of multiple drug therapy. The dentate gyrus (DG) normally functions as a filter. It prevents propagation of synchronized activity into the seizure-prone hippocampus. This filter or 'gatekeeper' attribute of the DG is compromised in temporal lobe epilepsy (TLE). In TLE, Mossy fibers (MF), the axons of granule cells, frequently sprout and aberrantly innervate the somatic and inner molecular layers of DG. Recurrent MF mediates reverberating excitation that can reduce the threshold for granule cell synchronization and, presumably facilitating participation of the DG in seizures. Recurrent MFs are known to be critically involved in temporal lobe epilepsy but they are only poorly understood. Unique property of MF is that they contain high concentrations of zinc (Zn2+), which is colocalized in synaptic vesicles and co-released with glutamate. Zn2+ has been implicated modulatory effects on a variety of ion channels, including attenuation of current through NMDA and GABA receptor-gated channels. In this study, pilocarpine-treated rats which become epileptic and develop a consistently dense recurrent MF pathway will be used to investigate and characterize the release of Zn2+ from recurrent MF about, which little information is available. We will also determine the translocation of MF released Zn2+ into granule cells. Proposed experiments are based on our previously published data and preliminary studies which have led to the need to complete these proposed highly feasible experiments. The outcome of the study will build foundation for future study on the action of released Zn2+ on neurotransmission as well as involvement of recurrent MF in TLE. The results will facilitate development of more rational, informed or targeted therapeutic strategies for epilepsy.