Regulation of AMPA Receptors by Ampakines

几条证据表明AMPA受体介导的快速兴奋性传递 调节BDNF的表达。从这一点预测，增加兴奋性突触后电流的大小与AMPA受体（ampakines）的阳性调节剂增加BDNF的表达在培养的脑切片和在体内。这些结果提高了使用AMPA受体调节剂来持续增加大脑中关键营养因子浓度的可能性。然而，使用一种新的培养切片技术进行突触反应的“慢性”记录的初步研究发现，ampakines在大约24 - 36小时后抑制兴奋性反应。随后的实验表明，抑郁症伴随着AMPA受体数量的显着减少， 膜组分Gall博士实验室的独立工作揭示了BDNF诱导的平行效应：长时间暴露导致培养的切片对ampakines不敏感。拟议的工作有五个与这些调查结果有关的目标。具体目标一将定义EPSP抑郁发作和恢复的时间过程。这些信息将与BDNF不应期的时间参数进行比较（见项目一）。具体目标二将检验AMPA受体的下调是EPSP抑制的原因这一假设。首先测量膜受体的数量和亲和力;随后的工作将测定受体亚基水平和周转率的变化。具体目标三涉及与EPSP有关的其他机制问题 抑郁症：触发事件是什么？连接AMPA受体激活与AMPA受体调节和BDNF表达的信号通路是否受到干扰？(Also项目一）。具体目标四研究AMPA受体下调的功能后果。将在效应发生之前和之后测试长期增强、长期抑制和癫痫发作易感性。在没有抑郁症的情况下，ampakine诱导的BDNF升高如何影响LTP的研究在项目三中描述。具体目标五将测试体内AMPA受体下调和信号传导的发生。总之，拟议的研究结果预计将产生新的和基本的信息AMPA受体调控。他们也被认为是关键的AMPA受体为基础的策略，用于上调一个关键的营养因子的发展。

Several lines of evidence indicate that fast excitatory transmission mediated by AMPA receptors regulates expression of BDNF. As predicted from this, increasing the size of excitatory postsynaptic currents with positive modulators of AMPA receptors (ampakines) increases BDNF expression both in cultured brain slices and in vivo. These results raise the possibility of using AMPA receptor modulators to produce sustained increases in the brain's concentration of a critical trophic factor. However, preliminary studies using a novel cultured slice technique for 'chronic' recording of synaptic responses led to the discovery that ampakines depress excitatory responses after about 24-36 hours. Follow on experiments showed that the depression is accompanied by a marked reduction in the number of AMPA receptors in membrane fractions. Separate work in the laboratory of Dr. Gall uncovered a parallel effect with regard to BDNF induction: prolonged exposure causes cultured slices to become refractory to ampakines. The proposed work has five objectives relating to these findings. Specific Aim One will define the time course for the onset of, and recovery from, EPSP depression. This information will be compared to the temporal parameters of the BDNF refractory period (see Project One). Specific Aim Two will test the hypothesis that down-regulation of AMPA receptors is responsible for EPSP depression. Number and affinity of the membrane receptors will be measured first; subsequent work will assay for changes in levels of receptor subunits and turnover. Specific Aim Three addresses additional mechanistic questions relating to EPSP depression: What are the triggering events? Are signaling pathways linking AMPA receptor activation to AMPA receptor regulation and BDNF expression disturbed? (Also see Project One). Specific Aim Four investigates the functional consequences of AMPA receptor down-regulation. Long term potentiation, long term depression, and seizure susceptibility will be tested prior to and after the onset of the effect. Studies on how LTP is affected by ampakine-induced elevation of BDNF in the absence of depression are described in Project Three. Specific Aim Five will test for the occurrence of AMPA receptor down-regulation and signaling in vivo. In all, the results of the proposed study are expected to yield new and fundamental information concerning AMPA receptor regulation. They are also expected to be critical in the development of an AMPA receptor based strategy for up-regulating a critical trophic factor.