Role of BCL-xL in synaptic plasticity in the hippocampus

BCL-2 家族蛋白在程序性细胞死亡的定型阶段发挥着重要作用。 BCL-2 家族蛋白有助于细胞死亡的发生或防止细胞死亡 死亡。 BCL-xL 是在大脑中表达的主要 BCL-2 家族成员，了解其 功能是设计神经保护策略的关键。 BCL-xL 的水平开始上升 突触正在大脑中形成。然而，在成人神经系统中，BCL-xL 水平仍然很高 即使没有死亡刺激，系统也会发挥作用，这促使我们假设 BCL-xL 发挥作用 在突触传递中发挥重要的生理作用。我们已经证明重组 BCLxL 注射到鱿鱼巨神经节的突触前末端会增加 突触受到刺激后释放的神经递质。 BCL-xL 的这种作用被模仿 注射 ATP，这会阻断注射 BCL-xL 的作用，表明 BCL-xL 可能 使更多的 ATP 可迅速用于突触传递。此外，当 BCL-xL 为 在培养的海马神经元中过度表达，它以线粒体为目标，定位这些 细胞器到突触，增加突触的数量和大小以及突触的速率 自发的神经递质释放事件。 高频后神经递质释放的短期和长期增强 刺激是在发育和神经可塑性过程中发生的经过充分研究的现象。 突触可塑性的一个重要形式是 CA3-CA 1 突触的长时程增强 (L TP) 在哺乳动物的海马体中。该部位的刺激引起的变化被认为是 记忆形成的过程。我们有强有力的初步证据支持 假设 BCl·xl 是调节长期增强作用所必需的 这个突触的神经传递。我们假设并有强有力的证据表明 BCl·xl 的作用机制是通过增加 ATP 的形成和释放 线粒体。在此应用中，我们将测试抑制 BCl·xl 或下调的概念 BCl-xl 表达的调节可防止 ATP 运行效率的提高 合酶复合物。我们假设这些改变是长期需要的 高频突触刺激后突触强度的变化，因此我们计划测试 抑制BCl·xl是否可以预防l TP。

BCL-2 family proteins playa major role in the commitment phase of programmed cell death. BCL-2 family proteins contribute either to the onset of cell death or to the protection against cell death. BCL-xL is the major BCL-2 family member expressed in brain, and understanding its function is key to designing strategies for neuroprotectlon. Levels of BCL-xL begin to rise just as synapses are forming in the brain. BCL-xL levels remain high, however, in the adult nervous system even in the absence of a death stimulus, prompting us to hypothesize that BCL-xL plays an important physiological role in synaptic transmission. We have shown that recombinant BCLxL injected into the presynaptic terminal of squid giant ganglion increases the amount of neurotransmitter released upon a stimulus to the synapse. This action of BCL-xL is mimicked by injection of ATP, which occludes the effects of injection of BCL-xL, suggesting that BCL-xL may make more ATP available acutely for synaptic transmission. Furthermore, when BCL-xL is overexpressed in cultured hippocampal neurons, it targets to mitochondria, localizes these organelles to synapses, increases the number and size of synapses and the rate of spontaneous neurotransmitter release events. Short and long term potentiation of neurotransmitter release after high frequency stimulation are well-studied phenomena that occur during development and in neural plasticity. An important form of synaptic plasticity is long term potentiation (L TP) at the CA3-CA 1 synapse in mammalian hippocampus. Changes induced by stimulation at this site are thought to underlie the processes of memory formation. We have strong preliminary evidence to support the hypothesis that BCl·xl is required for the modulation of long term potentiation of neurotransmission at this synapse. We hypothesize and have strong evidence that one mechanism of action of BCl·xl is to increase the formation and release of ATP by mitochondria. In this application, we will test the concept that inhibition of BCl·xl or down regulation of expression of BCl-xl prevents an increase in efficiency of operation of the ATP synthase enzyme complex. We hypothesize that these changes are required for long term changes in synaptic strength after high frequency synaptic stimulation, therefore we plan to test whether inhibition of BCl·xl prevents l TP.