BDNF Regulation: Roles in Plasticity and Neuroprotection

描述（由申请人提供）： 脑源性神经营养因子（BDNF）具有神经保护作用，促进轴突生长，并被认为在学习和对抗抑郁中发挥作用。因此，增加BDNF水平可能为治疗各种脑部疾病提供一种手段。申请人最近的工作发现AMPA型谷氨酸受体的正调节剂（“ampakines”）诱导BDNF表达。Ampakines可以穿过血脑屏障，在动物研究和临床试验中副作用最小。因此，他们提供了一个合理的手段操纵BDNF在大脑中的表达。然而，其他研究发现，长期应用（24-48小时）导致BDNF诱导变得难以治疗，并导致快速兴奋性反应的抑制，这表明可能存在谷氨酸受体活性的丧失。初步研究证实，长期的ampakine治疗会导致表面AMPA受体的损失。为了解决这个问题，申请人开发了一种开/关安巴金治疗方案，其维持升高的BDNF水平（20倍）数天。该计划项目建立在这些结果的基础上，并将解决三个广泛的目标：1）确定细胞通路，通过这些通路ampakines上调BDNF，诱导不应性，并下调快速，兴奋性传递; 2）测试内源性BDNF的作用是否与外源性BDNF的作用相似; 3）确定上调是否具有神经保护作用。项目1将设计最佳诱导BDNF的治疗方案，测试BDNF的增加是否与BDNF信号的增加有关，并测试BDNF水平增加防止缺血的假设。项目2将描述ampakine诱导的突触反应抑制的时间过程，并假设这是由于AMPA受体的下调。项目3将比较外源性BDNF与内源性BDNF增加对几种生理指标的影响，包括递质释放、突触可塑性和胆碱能驱动的EEG节律。BDNF与整合素粘附受体相互作用产生其作用的可能性也将被检查。项目4将使用与阿尔茨海默病相关的小鼠模型（ApoE -/-小鼠）来测试内源性BDNF是否抵消与年龄相关的病理，包括神经元缠结形成和淀粉样蛋白毒性。还将检查BDNF对胆碱能神经支配的影响。这四个项目将使用相同的实验制剂、治疗方法和核心设施。该计划有望为兴奋性受体和神经营养因子表达的调节提供新的见解。它还可以为治疗神经精神和神经病理疾病的新治疗策略提供基础。

DESCRIPTION (provided by applicant): Brain derived neurotrophic factor (BDNF) is neuroprotective, promotes axonal growth, and has been suggested to play roles in learning and counteracting depression. Increasing BDNF levels might, therefore, provide a means for treating various brain disorders. Recent work by the applicants discovered that positive modulators of AMPA-type glutamate receptors ('ampakines') induce BDNF expression. Ampakines cross the blood-brain barrier and have had minimal side effects in animal studies and clinical trials. Thus, they provide a plausible means for manipulating BDNF expression in brain. However, additional studies found that prolonged applications (24-48 h) cause BDNF induction to become refractory to treatment and led to a depression of fast excitatory responses suggesting that there may be a loss of glutamate receptor activity. Preliminary studies confirmed that prolonged ampakine treatment causes a loss of surface AMPA receptors. To obviate this problem, the applicants developed an on/off ampakine treatment regimen that sustains elevated BDNF levels (20-fold) for several days. The Program Project builds on these results and will address three broad objectives: 1) Identify cellular pathways through which ampakines up-regulate BDNF, induce refractoriness, and down-regulate fast, excitatory transmission; 2) Test if endogenous BDNF effects are similar to those of exogenous BDNF application; 3) Determine if up-regulation is neuroprotective. Project 1 will devise treatment regimens for optimally inducing BDNF, test if increased BDNF is associated with increased BDNF signaling and test the hypothesis that increased BDNF levels protect against ischemia. Project 2 will characterize the time course of ampakine-induced depression of synaptic responses and the hypothesis that this is due to a down regulation of AMPA receptors. Project 3 will compare the effects of exogenous BDNF with increases in endogenous BDNF on several physiological measures including transmitter release, synaptic plasticity, and cholinergically driven EEG rhythms. The possibility that BDNF interacts with integrin adhesion receptors to produce its effects will also be examined. Project 4 will use a mouse model pertinent to Alzheimer's disease (ApoE -/- mice) to test if endogenous BDNF counteracts age-related pathologies including neurofibrillary tangle formation and amyloid toxicity. Effects of BDNF on cholinergic innervation will also be examined. The four projects will use the same experimental preparations, treatments and core facilities. The program is expected to provide new insights into the regulation of excitatory receptors and neurotrophin expression. It could also provide foundations for a new therapeutic strategy for treatment of neuropsychiatric and neuropathological disorders.