Multivesicular synaptic release

描述（由申请人提供）：CNS中的细胞间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汇集等现象表明，神经元之间的点对点突触通信并不是CNS中信息传递的唯一方法。递质的溢出和汇集是否发生取决于几个变量，包括每个突触和每个突触前动作电位释放的递质量。如果清除机制被释放所压倒，递质将从突触扩散出去。在某些突触，增加囊泡释放概率的操作导致单个突触前动作电位后单个突触释放多个囊泡。这种大剂量的发射器可以压倒当地的运输工具，并导致溢出。然而，在其他突触，多囊泡释放尚未被发现，无论释放的概率，这表明有一种机制，防止释放超过一个单一的囊泡。递质溢出和汇集至少部分负责激活突触外受体，包括代谢型受体，这反过来又是几种类型的短期和长期可塑性所需的。这项建议的主要目标是确定可塑性在多大程度上取决于发射器溢出和溢出的程度取决于多泡释放。这将通过结合电生理学和光学技术来研究三种不同的突触来实现，每种突触都具有不同的特征。我们的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。所有的中枢神经系统功能，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。传播的基本分子和细胞特性的知识是在病理状态下合理干预的发展所必需的。

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.