BDNF AND HIPPOCAMPAL HYPEREXCITABILITY

描述：(申请人摘要) 脑源性神经营养因子促进生长和存活 不同系统中的几种类型的神经元。此外，BDNF还拥有 已被证明能增强兴奋性突触在培养和 在脑片上。在海马区，脑源性神经营养因子染色最强 支配海马区的齿状回颗粒细胞苔藓纤维轴突 CA3锥体细胞。我们最近发现，暴露在BDNF中 增强大鼠脑内CA3区锥体细胞颗粒细胞兴奋 海马片。在这种情况下，重复刺激 颗粒细胞可导致ARE CA3癫痫样行为。这些 影响是选择性的，因为其他输入的激励不是 增强版。所有的作用都被一种非特异性的酪氨酸激酶所阻断 TrkB的抑制物，被认为是介导BDNF的受体 效果。 拟议的研究将讨论BDNF是否有应有的影响 增加兴奋或减少抑制。他们将讨论是否 脑源性神经营养因子的作用部位是突触前或突触后。潜力 脑源性神经营养因子对过度兴奋性的贡献将基于 上述观察结果以及BDNF信息、蛋白质和受体是 因癫痫发作而增加。我们预测，这种诱导会增加BDNF的 癫痫发作后的潜在动作，并可能导致反复发作 慢性癫痫发作的性质。BDNF也可能有助于 发芽后癫痫发作，因为苔藓纤维形成新的突触 在这种情况下的齿状回。因为发芽发生在 几种癫痫的动物模型，在许多颞叶癫痫患者中， 这些研究对理解这些因素具有重要意义。 有助于癫痫的发生。最后，我们将讨论可能的 脑源性神经营养因子和兴奋毒性之间的因果联系，这是由 几个易受伤害的亚群是BDNF的目标- 免疫反应纤维，但抗性细胞不是。这些研究将 确定内源性神经营养因子，被认为是如何 主要是神经保护，可以影响正常和异常的活动 在边缘系统中。

DESCRIPTION: (Applicant's abstract) Brain-derived neurotrophic factor (BDNF) promotes growth and survival of several types of neurons in diverse systems. In addition, BDNF has been shown to enhance excitatory synaptic transmission in culture and in brain slices. In the hippocampus, BDNF staining is strongest in the mossy fiber axons of dentate gyrus granule cells, which innervate area CA3 pyramidal cells. We have recently found that exposure to BDNF enhances granule cell excitation of area CA3 pyramidal cells in hippocampal slices. Under these conditions, repetitive stimulation of granule cells can lead to epileptiform behavior in are CA3. These effects are selective in that excitation by other inputs are not enhanced. All effects are blocked by a nonspecific tyrosine kinsase inhibitor of trkB, the receptor that is thought to mediate BDNF's effects. The proposed studies will address whether the effects of BDNF are due to increased excitation or reduced inhibition. They will address whether BDNF's site of action is pre- or postsynaptic. The potential contribution of BDNF to hyperexcitability will be addressed, based on the above observations, and that BDNF message, protein, and receptor are increased by seizures. We predict that this induction increases BDNF's potential actions after seizures, and could contribute to the repetitive nature of seizures in chronic epilepsy. BDNF may also contribute to seizures after "sprouting," because mossy fibers form novel synapses in the dentate gyrus under these conditions. Because sprouting occurs in several animal models of epilepsy, and in many temporal lobe epileptics, these studies have implications for understanding the factors contributing to epileptogenesis. Finally, we will address the possible causal link between BDNF and excitotoxicity, a link suggested by the fact that several vulnerable subpopulations are targets of BDNF- immunoreactive fibers, but resistant cells are not. These studies will establish how an endogenous neurotrophin, considered to be neuroprotective primarily, can influence normal and abnormal activity in the limbic system.