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，谷氨酸被储存在囊泡中并从囊泡中释放出来。随后，它在突触间隙扩散，并与突触后受体相互作用。因此，了解它是如何在有限的空间中运输以及它如何与受体相互作用是至关重要的。过去尝试了几种方法来模拟递质在突触间隙中的扩散以及它们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，例如谷氨酸和水分子在受限空间的壁上分层。作为分层的结果，界面谷氨酸-突触壁间的相互作用在减缓扩散方面变得非常重要。谷氨酸和水分子不仅是层状的，而且在壁面附近也是有序的。拟议的研究应该评估这种有序性如何影响谷氨酸与AMPA受体的结合，这应该会加强我们在原子水平上对这种过程的理解。不仅扩散常数，而且还有其他各种因素，如间隙的宽度和长度，AMPA通道的门控动力学速度，释放的分子数量，影响微小的快速兴奋性突触后电流(MEPSCs)的幅度和时间过程，从而影响量子大小，这与量子含量一起决定了突触的有效性。它们也会影响它们目前的波动，但不同。这将通过模拟和实验在大鼠海马锥体神经元中进行详细探索。此外，现在很明显，mEPSC及其当前的波动是动态丰富的。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当前波动，并将其适应于其生成模型，则至少可以从单个mEPSC来评估形成mEPSC的一些因素的值。

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.