Effects of Elevating Brain Derived Neurotrophic Factor on Hippocampal Physiology

脑源性神经营养因子（BDNF）引起海马片谷氨酸突触递质释放适度增加和长期增强（LTP）的显著促进。申请人的工作表明，它也对由胆碱能中隔-海马投影引发的节律有深远的影响。拟议的研究将确定BDNF的上调是否再现外源性BDNF获得的效果。第二个目标是验证BDNF对LTP的影响取决于属于整合素家族的粘附受体的激活这一假设。ampa型谷氨酸受体（ampakines）的阳性调节剂将用于增加培养海马切片中BDNF的产生。当AMPA受体药物被冲洗干净，BDNF蛋白水平大大高于控制水平后，进行生理测试。具体目标1验证了这样的预测：在高频刺激下，BDNF的增加将伴随着配对脉冲促进性的降低和对“突触疲劳”的更大抵抗。BDNF的trkB受体抑制剂将在本实验和后续实验中使用，以证实安帕平治疗的结果取决于神经营养因子。Specific Aim #2研究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。这个实验与项目二的一个组成部分密切相关。特异性目标#3比较了胆碱能诱导的BDNF升高切片与BDNF升高切片的β节律

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.