Role of Bcl-xl in synaptic plasticity in the hippocampus

描述（由申请人提供）：在海马Schaffer侧支到CA 1突触，突触传递的长期增强可能是记忆储存的基础。在阿尔茨海默氏病、帕金森氏病和其他神经退行性疾病中，随着突触衰退或缩回，突触强化可能变得功能障碍。频繁活动后突触可塑性的一个重要方面是AMPA受体插入突触后质膜的增强。然而，除了突触后的变化之外，还发生了持久的突触前变化。在发育过程中，囊泡池的大小增加，以处理更频繁发生的突触事件，但长期持久的突触前可塑性在成人CA 1突触后的高频事件的作用还没有完全研究。突触前可塑性的一种形式是囊泡恢复为易于释放的池的速率的长期持续变化。在突触活动期间，用于释放的囊泡的可用性减少表现为突触抑制;突触抑制后囊泡池恢复的速率影响突触的响应能力，因此适合于可塑性。我们以前已经发现，抗死亡蛋白Bcl-xL不仅可以防止神经元的体细胞死亡，而且可以防止突触抑制急性和长期。Bcl-xL的部分功能是提高突触囊泡的易释放池的恢复速率。我们最近的初步数据表明，Bcl-xL直接结合到囊泡膜，提高突触活动期间囊泡从质膜再摄取的速率。除了囊泡再摄取，然而，我们的数据还表明，Bcl-xL，通过其调节突触代谢，可能会影响动员囊泡从储备池。本申请的假设是Bcl-xL通过增强线粒体效率以增加突触囊泡储备池的动员而引起突触强度的长期变化。在这项建议中，我们将研究急性和长期的变化，线粒体效率的ATP水平和氧摄取的测量正在进行的变化，在活的突触前扣接受刺激海马神经元在培养和体内。使用成像和记录技术，我们将区分Bcl-xL对质膜上囊泡再摄取的影响和对储备池动员的影响，以确定线粒体效率对不同囊泡再积累策略的影响。我们还将研究Bcl-x对神经元兴奋性抑制引起的囊泡池抑制长期变化的影响。与活性降低相反，增加的突触活性可能与增强的ATP可用性相关，直接促进磷酸化和下游靶点的激活，例如突触蛋白，其快速地将囊泡从储备释放到容易释放的池。我们的研究将揭示在学习和记忆过程中加强突触或在突触功能障碍或神经退行性变过程中削弱突触的基本特性。

DESCRIPTION (provided by applicant): At the hippocampal Schaffer collateral to CA1 synapse long term enhancement of synaptic transmission may underlie memory storage. Synaptic strengthening can become dysfunctional in Alzheimer's disease, Parkinson's Disease and other neurodegenerative disorders as synapses decline or are retracted. One important aspect of synaptic plasticity after frequent activity is the enhanced insertion of AMPA receptors into the postsynaptic plasma membrane. In addition to postsynaptic changes, however, long lasting presynaptic changes occur. During development vesicle pool sizes increase to handle more frequently occurring synaptic events, but the role of long lasting presynaptic plasticity at the adult CA1 synapse after high frequency events has been incompletely studied. One form of presynaptic plasticity is a long lasting change in the rate at which vesicles recover to readily releasable pools. During synaptic activity, a decrease in availability of vesicles for release manifests as synaptic depression; the rate at which vesicle pools recover after synaptic depression affects the response capabilities of the synapse and is therefore amenable to plasticity. We have found previously that the anti-death protein Bcl-xL acts not only to prevent somatic death in neurons, but to prevent synaptic depression acutely and over the long term. In part Bcl-xL functions to enhance the rate of recovery of the readily releasable pool of synaptic vesicles. Our recent preliminary data show that Bcl-xL binds directly to vesicle membranes, enhancing the rate of vesicle re-uptake from the plasma membrane during synaptic activity. In addition to vesicle re-uptake, however, our data also show that Bcl-xL, by its regulation of synaptic metabolism, may affect mobilization of vesicles from the reserve pool. The hypothesis of this application is that Bcl-xL causes long term changes in synaptic strength by enhancing mitochondrial efficiency to increase mobilization of a reserve pool of synaptic vesicles. In this proposal, we will study acute and long term changes in mitochondrial efficiency by measuring ongoing changes in ATP levels and oxygen uptake in living presynaptic boutons undergoing stimulation in hippocampal neurons both in culture and in vivo. Using imaging and recording techniques, we will differentiate the effects of Bcl-xL on vesicle re-uptake at the plasma membrane from those on reserve pool mobilization to determine the effect of mitochondrial efficiency on different vesicle re-accumulation strategies. We will also study the effects of Bcl-x on long term changes in vesicle pool depression brought on by inhibition of neuronal excitability. In contrast to decreased activity, increased synaptic activity may be associated with enhanced ATP availability, directly promoting phosphorylation and activation of downstream targets such as synapsin that rapidly release vesicles from the reserve to the readily releasable pool. Our studies will shed light on basic properties that strengthen the synapse during learning and memory or weaken it during synaptic dysfunction or neurodegeneration.