Effects of Elevating Brain Derived Neurotrophic Factor on Hippocampal Physiology

提高脑源性神经营养因子对海马生理的影响

• 批准号: 6695486
• 负责人: GARY S LYNCH
• 金额: $ 23.63万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6695486
• 关键词: AMPA receptors; NMDA receptors; brain derived neurotrophic factor; electrophysiology; hippocampus; infant animal; laboratory rat; long term potentiation; neural plasticity; neurophysiology; receptor expression; synapses

Brain Derived Neurotrophic Factor (BDNF) causes a modest increase in transmitter release and a marked facilitation of long-term potentiation (LTP) at glutamatergic synapses in hippocampal slices. Work by the applicants indicates that it also has a profound effect on rhythms triggered by the cholinergic septo-hippocampal projections. The proposed studies will determine if up-regulation of BDNF reproduces the effects obtained with exogenous BDNF. A second goal is to test the hypothesis that BDNF's effects on LTP depend on activation of adhesion receptors belonging to the integrin family. Positive modulators of AMPA-type glutamate receptors (ampakines) will be used to increase BDNF production in cultured hippocampal slices. Physiological tests will be carried out after AMPA receptor drugs have been washed out and BDNF protein levels are greatly elevated above control. Specific Aim #1 tests the prediction that increased BDNF will be accompanied by reduced paired pulse facilitation and greater resistance to 'synaptic fatigue' during high frequency stimulation. Inhibitors of BDNF's trkB receptor will be used in this and subsequent experiments to confirm that the consequences of ampakine treatments depend on the neurotrophin. Specific Aim #2 examines post-synaptic functioning and plasticity including the NMDA components of synaptic responses and the induction / expression of LTP. This experiment is closely related to a component of Project Two. Specific Aim #3 compares cholinergically induced beta-rhythms in BDNF elevated slices with those in yoked controls (collaboration with Project 4). Recently discovered spontaneous rhythms will be used to determine if BDNF's effects are selective to cholinergic modulation. Specific Aim #4 will test if (a) the enhanced LTP caused by BDNF is blocked by integrin antagonists and (b) BDNF activates integrins. Specific Aim #5 tests the prediction that acute (6 hrs) and chronic (5 days) increases in BDNF protein content will be associated with different changes in synaptic physiology. Chronic increases in BDNF protein in Aim #5 will be induced with spaced applications of ampakines (see Project One). Together these studies will 1) provide a first description of the physiological changes that accompany pharmacologically-elevated endogenous BDNF levels, 2) explore a novel route whereby the neurotrophin could regulate plasticity, and 3) address issues that are critical to the clinical use of AMPA receptor modulators.

脑源性神经营养因子 (BDNF) 会导致递质释放适度增加，并显着促进海马切片谷氨酸能突触的长时程增强 (LTP)。申请人的工作表明，它对胆碱能间隔海马投射触发的节律也有深远的影响。拟议的研究将确定 BDNF 的上调是否能重现外源 BDNF 所获得的效果。第二个目标是检验以下假设：BDNF 对 LTP 的影响取决于属于整合素家族的粘附受体的激活。 AMPA 型谷氨酸受体（ampakines）的正调节剂将用于增加培养的海马切片中 BDNF 的产生。当AMPA受体药物被洗掉并且BDNF蛋白水平大大高于对照后，将进行生理测试。具体目标#1 测试了这样的预测：BDNF 的增加将伴随着配对脉冲促进的减少以及高频刺激期间对“突触疲劳”的更强的抵抗力。 BDNF trkB 受体抑制剂将用于本次实验和后续实验，以确认安帕金治疗的效果取决于神经营养素。具体目标#2 检查突触后功能和可塑性，包括突触反应的 NMDA 成分和 LTP 的诱导/表达。该实验与项目二的一个组成部分密切相关。具体目标 #3 将 BDNF 升高切片中胆碱能诱导的 β 节律与 轭式控制（与项目 4 合作）。最近发现的自发节律将被用来确定 BDNF 的作用是否对胆碱能调节具有选择性。具体目标 #4 将测试 (a) BDNF 引起的增强 LTP 是否被整合素拮抗剂阻断以及 (b) BDNF 激活整合素。具体目标#5测试了BDNF蛋白含量的急性（6小时）和慢性（5天）增加将与突触生理学的不同变化相关的预测。间隔应用安帕金会诱导目标 #5 中 BDNF 蛋白的慢性增加（参见项目一）。这些研究共同将 1）提供 首先描述了伴随药理学升高的内源性 BDNF 水平而发生的生理变化，2）探索神经营养蛋白调节可塑性的新途径，3）解决对 AMPA 受体调节剂临床使用至关重要的问题。