Multivesicular synaptic release

描述（由申请人提供）：在中枢神经系统中，细胞间的信息传递被认为发生在与相邻突触隔离的单个突触上。然而，突触之间的递质溢出和池化等现象表明，神经元之间的点对点突触通信并不是中枢神经系统中信息传递的唯一方法。是否发生递质溢出和池化取决于几个变量，包括每个突触每个突触前动作电位释放的递质数量。如果清除机制被释放所淹没，递质就会从突触中扩散出去。在某些突触，增加囊泡释放概率的操作导致单个突触在单个突触前动作电位下释放多个囊泡。这种大量的传送器会压倒当地的传送器，并导致溢出效应。然而，在其他突触中，无论释放概率如何，均未发现多囊泡释放，这表明存在一种阻止多个囊泡释放的机制。递质溢出和池化至少在一定程度上负责突触外受体的激活，包括代谢受体，而代谢受体又是多种类型的短期和长期可塑性所必需的。本提案的主要目标是确定可塑性在多大程度上取决于传递器溢出，以及溢出在多大程度上取决于多泡释放。这将通过电生理和光学技术的结合来完成，研究三个不同的突触，每个突触都有不同的特征。该计划是利用这些突触的属性来探测，首先，多泡释放的普遍性，其次，其后果的多样性。所有中枢神经系统的功能，包括感觉处理、运动行为、意识和记忆，都依赖于完整的突触传递。对传播的基本分子和细胞特性的了解是在病理状态下进行合理干预的必要条件。

DESCRIPTION (provided by applicant): Cell-to-cell transmission of information in the CNS is thought to occur at individual synapses, isolated from their neighbors. However, phenomena such as transmitter spillover and pooling between synapses have suggested that point-to-point synaptic communication between neurons is not the only method of information transfer in the CNS. Whether spillover and pooling of transmitter occurs depends on several variables including the amount of transmitter released per synapse per presynaptic action potential. If clearance mechanisms are overwhelm by release, transmitter will spread away from synapses. At some synapses, manipulations that increase the probability of vesicular release result in the release of multiple vesicles from individual synapses following single presynaptic action potentials. This large bolus of transmitter can overwhelm local transporters and result in spillover. At other synapses, however, multivesicular release has not been found regardless of the release probability suggesting that there is a mechanism that prevents release of more than a single vesicle. Transmitter spillover and pooling are at least in part responsible for activation of extrasynaptic receptors including metabotropic receptors which in turn are required for several types of short and long term plasticity. The main objectives of this proposal are to determine the extent to which plasticity depends on transmitter spillover and the degree to which spillover depends on multivesicular release. This will be accomplished using a combination of electrophysiological and optical techniques in the study of three different synapses each with distinct characteristics. The plan is to use the attributes of each of these synapses to probe, first, the generality of multivesicular release and, second, the multiplicity of its consequences. All CNS functions including sensory processing, motor behavior, consciousness, and memory depend on intact synaptic transmission. Knowledge of the fundamental molecular and cellular properties of transmission is required for the development of rational interventions in pathological states.