Role of BCL-xL in synaptic plasticity in the hippocampus

BCL-2家族蛋白在细胞程序性死亡的承诺期发挥重要作用。 BCL-2家族蛋白参与细胞死亡的发生或对细胞的保护 死亡。BCL-XL是脑内表达的主要BCL-2家族成员，对其了解 功能是设计神经保护策略的关键。Bcl-xl水平开始上升，就像 大脑中正在形成突触。然而，在成年神经症患者中，bcl-xl水平仍然很高。 系统甚至在没有死亡刺激的情况下，促使我们假设bcl-xl发挥作用 在突触传递中起重要的生理作用。我们已经证明了重组BCLxL 注射入鱿鱼巨神经节突触前终末可增加 神经递质在刺激突触时释放。BCL-XL的这个动作是通过以下方式模仿的 注射三磷酸腺苷阻断bclxl的作用，提示bclxl可能 让更多的三磷酸腺苷迅速用于突触传递。此外，当bcl-xl是 在培养的海马神经元中过表达，它针对线粒体，定位于这些 细胞器连接到突触，增加突触的数量和大小，以及 自发的神经递质释放事件。 高频刺激对神经递质释放的短期和长期增强作用 刺激是在发育和神经可塑性过程中发生的被广泛研究的现象。 突触可塑性的一种重要形式是突触的长时程增强(L TP) 在哺乳动物的海马体中。这个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 BCL·XL是长时程增强调制所必需的假设 这个突触的神经传递。我们假设并有强有力的证据证明 BCL·XL的作用机制是通过以下途径促进ATP的形成和释放 线粒体。在本应用中，我们将测试bcl.xl或down抑制的概念 调控bc1-xl的表达阻止了ATP运行效率的提高 合酶酶复合体。我们假设这些变化是长期需要的。 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.