Excitatory synaptic transmission in CNS

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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.