POSTISCHEMIC MENTAL RETARDATION--REVERSING NEURON DAMAGE

拟议的研究将评估生理和 皮层内发生的超微结构变化 神经元对缺血的反应。 缺氧缺血 受伤是最重要的神经问题 发生在围产期。 在任何时候， 早期发育会导致终生的神经功能缺陷 包括智力迟钝癫痫和脑瘫 长 这项研究的长期目标是提高对 突触可塑性和修复的过程，并开发方法 干预，将突触可塑性和修复， 开发干预方法，优化修复。 的 拟议中的研究将检验皮质突触 可受到缺血的可逆和不可逆影响， 将确定一些与 缺血性损伤的可逆性。 啮齿类动物的锥体细胞 选择海马CA1进行研究是因为其 已知的对局部缺血的选择性脆弱性和它们 产生长时程增强作用。 长时程增强（LTP） 一种增强的突触反应，由短暂的 高频传入刺激 这项研究旨在 建立一个皮质缺血的体外模型，使用 海马切片制备，这将允许生理和 可靠地产生缺血的超微结构效应。 一个 体外制备可更好地控制 缺血和再灌注比在完整的动物。 具体地说， 所提出的实验被设计来确定：1） 短暂缺血所需的最短时间 消除切片中的诱发反应; 2） 缺血，细胞可以忍受，仍然恢复任何诱发的 反应;和3）可以被治疗的缺血的最长时间 并允许LTP的恢复。 恢复 如果LTP可以被诱发，则认为缺血是完全的。 缺血前水平 将进行超微结构分析， 在相同的材料上进行， 影响突触的密度和形态 我们将尝试 突触超微结构的变化与 电生理恢复通过比较 在发育组织中恢复到成人中，我们将测试 假设修复过程更广泛， 发育中的组织 随后，将使用体外模型 量化药理学和生理学的影响 提高不可逆转损害的门槛， 成年和发育中的海马组织，以评估任何 年龄依赖性差异， 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.