BDNF AND HIPPOCAMPAL HYPEREXCITABILITY

描述：（申请人摘要） 脑源性神经营养因子（BDNF）促进生长和存活 在不同的系统中的几种类型的神经元。此外，BDNF 在培养物中显示出增强兴奋性突触传递， 在大脑切片中。在海马体中，BDNF染色最强， 齿状回颗粒细胞的苔藓纤维轴突，支配区域 CA 3锥体细胞。我们最近发现接触BDNF 增强CA 3区锥体细胞的颗粒细胞兴奋， 海马切片。在这种情况下，重复刺激 颗粒细胞可导致CA 3区癫痫样行为。这些 效应是选择性的，因为其他输入的激励不 增强所有作用都被一种非特异性酪氨酸激酶阻断 trkB的抑制剂，被认为是介导BDNF的受体 方面的影响. 拟议的研究将解决BDNF的影响是否是由于 增加兴奋或减少抑制。他们将讨论是否 BDNF的作用部位是突触前或突触后。的潜在 BDNF对过度兴奋的贡献将根据以下内容进行讨论： 上述观察结果以及BDNF信息、蛋白质和受体被 因癫痫发作而增加。我们预测，这种诱导增加了BDNF的 癫痫发作后的潜在行动，并可能有助于重复 慢性癫痫的发作性质。BDNF也可能有助于 癫痫发作后“发芽”，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 几种癫痫动物模型，以及许多颞叶癫痫患者， 这些研究对于理解这些因素有着重要意义， 会导致癫痫最后，我们将讨论可能的 BDNF和兴奋性毒性之间的因果关系， 事实上，几个脆弱的亚群是BDNF的目标- 免疫反应纤维，但抵抗细胞没有。这些研究将 确定内源性神经营养因子，被认为是 主要是神经保护，可以影响正常和异常的活动 大脑边缘系统

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.