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疾病，影响美国约1%的人口。虽然癫痫通常是可以用药物治疗的，但大约25%-30%的癫痫患者在接受多种药物治疗的情况下仍会反复发作。齿状回(DG)通常起滤器的作用。它防止同步活动传播到容易癫痫发作的海马体。在颞叶癫痫(TLE)中，DG的这种过滤器或“把关人”属性受到损害。在TLE中，颗粒细胞的轴突苔藓纤维(Mf)经常出芽，并异常地支配DG的体细胞层和内分子层。反复发作的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DG参与癫痫发作。众所周知，复发的MFS与颞叶癫痫密切相关，但人们对此知之甚少。MF的独特性质是它们含有高浓度的锌，锌离子共存于突触小泡中，并与谷氨酸共同释放。锌离子对多种离子通道具有调制作用，包括通过NMDA和GABA受体门控通道的电流衰减。在这项研究中，匹罗卡品治疗的大鼠成为癫痫并发展出持续致密的复发性MF通路，将被用来研究和表征关于复发性MF的锌离子的释放，这方面的信息很少。我们还将确定MF释放的锌离子在颗粒细胞中的移位。建议的实验是基于我们之前公布的数据和初步研究，这些数据和初步研究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在神经传递中的作用以及复发性多发性肌炎在TLE中的作用奠定了基础。这一结果将有助于开发更合理、更知情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.