POSTISCHEMIC MENTAL RETARDATION--REVERSING NEURON DAMAGE

拟议的研究将评估生理和 大脑皮层内发生的超微结构变化 突触上的神经元对缺血作出反应。缺氧-缺血 损伤是唯一最重要的神经问题。 发生在围产期。它在任何时候出现在 早期发育可导致终生神经缺陷 包括智力低下、癫痫发作和脑瘫。长 这项研究的学期目标是提高对 突触的可塑性和修复过程，以及发展方法 对突触的可塑性和修复进行干预，并 制定干预方法，以优化修复。这个 拟议的研究将检验这一假设，即皮质突触 可受缺血的可逆和不可逆的影响，以及 我将标识一些与 缺血性损伤的可逆性。啮齿动物的锥体细胞 海马区CA1区之所以被选为研究对象是因为 已知的对缺血的选择性易感性及其能力 产生长期增强效应。长时程增强(LTP)是 一种增强的突触反应，由短暂的突触爆发引起 高频传入刺激。这项研究旨在 建立大脑皮层缺血的体外模型 海马区切片准备，这将允许生理学和 缺血的超微结构效应要可靠地产生。一个 体外制剂提供了更好的控制持续时间 缺血和再灌流效果优于完整动物。具体来说， 拟议的实验旨在确定：1) 短暂性脑缺血所需的最短时间 取消脑片中的诱发反应；2)最大周期 细胞可以忍受的缺血，并且仍然可以恢复任何诱发的 反应；以及3)最长的缺血期 忍受了，仍然允许LTP的恢复。从以下方面恢复 如果可以在以下时间诱发LTP，则认为缺血已完成 缺血前水平。超微结构分析将是 在相同的材料上进行检查，以检查缺血 影响突触密度和形态。我们将尝试 突触超微结构改变与脑损伤程度的关系 电生理恢复。通过比较这一过程， 在发育中的组织恢复到成人的水平，我们将测试 修复过程更广泛的假说 发育中的组织。随后，将使用体外模型 为了量化药理和生理学的作用 提高不可逆损害阈值的干预措施 成体和发育中的海马区组织 治疗反应的年龄差异 干预。

The proposed research will evaluate the physiological and ultrastructural changes that take place within the cortical neuron at the synapse in response to ischemia. Hypoxic-ischemic injury is the single most important neurological problem occurring in the perinatal period. Its presence at any time in early development can lead to lifelong neurologic deficits including mental retardation, seizures, and cerebral palsy. Long term goals of this research are to improve knowledge about process of synaptic plasticity and repair, and to develop methods of intervention that will synaptic plasticity and repair, and to develop methods of intervention that will optimize repair. The proposed studies will test the hypothesis that cortical synapses can be both reversibly and irreversibly affected by ischemia, and will identify some of the features that are related to the reversibility of ischemic injury. The pyramidal cells of rodent hippocampal CA1 have been chosen for study because of their known selective vulnerability to ischemia and their ability to produce long term potentiation. Long term potentiation (LTP) is an enhanced synaptic response that results from brief bursts of high frequency afferent stimulation. This research is designed to develop an in vitro model of cortical ischemia, using the hippocampal slice preparation, that will allow for physiologic and ultrastructural effects of ischemia to be reliably produced. An in vitro preparation affords better control of the duration of ischemia and reperfusion than in the intact animal. Specifically, the proposed experiments have been designed to determine: 1) the minimum duration of ischemia necessary to transiently abolish evoked responses in the slice; 2) the maximum period of ischemia that the cells can endure and still recover any evoked response; and 3) the maximum period of ischemia that can be endured and still allow for the recovery of LTP. Recovery from ischemia will be considered complete if LTP can be elicited at preischemic levels. An ultrastructural analysis will be performed on the same material to examine how ischemia affects synaptic density and morphology. We will attempt to correlate synaptic ultrastructural changes with the degree of electrophysiologic recovery. By comparing the process of recovery in developing tissue to that in the adult, we will test the hypothesis that repair processes are more extensive in developing tissue. Subsequently, the in vitro model will be used to quantify the effects of pharmacologic and physiologic interventions in raising the threshold for irreversible damage in adult and developing hippocampal tissue in order to assess any age dependent differences in response to therapeutic intervention.