Excitatory synaptic transmission in CNS

谷氨酸是脊椎动物中枢神经系统中主要的兴奋性突触递质，因此在整个中枢神经系统中，该物质储存在囊泡中并从囊泡中释放。它随后在突触间隙中扩散并与突触后受体相互作用。因此，了解它如何在密闭空间中运输以及如何与受体相互作用至关重要。过去尝试了几种方法来模拟突触间隙中递质的扩散及其与突触后受体的相互作用。然而，最近的分子动力学模拟揭示了意想不到的复杂性，例如密闭空间壁附近的谷氨酸盐和水分子分层。作为分层的结果，界面谷氨酸-突触壁相互作用在减缓扩散中变得非常重要。谷氨酸和水分子不仅是分层的，而且在壁附近也是有序的。拟议的研究应该评估这种排序如何影响谷氨酸与AMPA受体的结合，这应该增强我们对原子尺度上这种过程的理解。不仅扩散常数，但各种其他因素，如裂缝的宽度和长度，AMPA通道的门控的动力学速率，释放的分子数量，影响的幅度和时间过程的微型快速兴奋性突触后电流（mEPSC），从而量子大小，这与量子内容一起决定突触功效。它们也会影响电流波动，但不同。这将详细探讨模拟和实验在大鼠海马锥体神经元。此外，现在清楚的是，mEPSC及其电流波动是动力学丰富的。这提出了一种令人兴奋的可能性，即如果同时考虑mEPSC的幅度、其上升和衰减时间以及其电流波动并将其拟合到其生成模型中，则可以从单个mEPSC评估至少一些形成mEPSC的因素的值。

Glutamate is the major excitatory synaptic transmitter in vertebrate central nervous system and therefore all over the central nervous system the agent is stored in and released from vesicles. It subsequently diffuses in the synaptic cleft and interacts with post-synaptic receptors. It is thus critically important to understand how it is transported in the confined space and how it interacts with the receptors. Several approaches were tried in the past to simulate diffusion of transmitters in the synaptic cleft and their interaction with post-synaptic receptors. However, recent molecular dynamics simulations revealed unexpected complexities, such as layering of glutamate and water molecules near the wall of the confined space. As a result of layering the interfacial glutamate-synaptic wall interactions become very important in slowing diffusion. Glutamate and water molecules are not only layered but are also ordered near the wall. Proposed studies should evaluate how such ordering affects the glutamate binding to AMPA receptors, which should enhance our understanding of such processes on the atomic scale. Not only diffusion constant but a variety of other factors, such as cleft width and length, kinetic rates of gating of AMPA channels, number of molecules released, influence the amplitude and time course of miniature fast-excitatory post-synaptic currents (mEPSCs), and thus the quantal size, which together with the quantum content determines the synaptic efficacy. They also influence their current fluctuations, but differently. This will be explored in detail by simulations and experimentally in rat hippocampal pyramidal neurons. Moreover, it is now clear that the mEPSCs and their current fluctuations are kinetically rich. This raises an exciting possibility that the values of at least some factors shaping mEPSCs can be evaluated from individual mEPSCs, if the amplitude of an mEPSC, its rise and decay time, but also its current fluctuations, are considered simultaneously and fitted to the model of its generation.