Abstract
Besides the geometrical tortousity due to the extrasynaptic structures, macromolecular crowding and geometrical irregularities constituting the cleft composition at central excitatory synapses has a major and direct role in retarding the glutamate diffusion within the cleft space. However, the cleft composition may not only coarsely reduce the overall diffusivity of the glutamate but may also lead to substantial spatial variation in the diffusivity across the cleft space. Decrease in the overall diffusivity of the glutamate may have straightforward consequences to the glutamate transients in the cleft. However, how spatial variation in the diffusivity may further affect glutamate transients is an intriguing aspect. Therefore, to understand the role of cleft heterogeneity, the present study adopts a novel approach of glutamate diffusion which considers a gamma statistical distribution of the diffusion coefficient of glutamate (Dglut) across the cleft space, such that its moments discernibly capture the dual impacts of the cleft composition, and further applies the framework of superstatistics. The findings reveal a power law behavior in the glutamate transients, akin to the long-range anomalous subdiffusion, which leads to slower decay profile of cleft glutamate at higher intensity of cleft heterogeneity. Moreover, increase in the cleft heterogeneity is seen to eventually cause slower-rising excitatory postsynaptic currents with higher amplitudes, lesser noise, and prolonged duration of charge transfer across the postsynaptic membrane. Further, with regard to the conventional standard diffusion approach, the study suggests that the effective Dglut essentially derives from the median of the Dglut distribution and does not necessarily need to be the mean Dglut. Together, the findings indicate a strong implication of cleft heterogeneity to the metabolically cost-effective tuning of synaptic response during the phenomenon of plasticity at individual synapses and also provide an additional factor of variability in transmission across identical synapses.
Highlights
The phenomenon of synaptic transmission at central excitatory synapses plays an extremely crucial role in the functioning of the central nervous system
To understand the role of cleft heterogeneity, the present study adopts a novel approach of glutamate diffusion which considers a gamma statistical distribution of the diffusion coefficient of glutamate (Dglut) across the cleft space, such that its moments discernibly capture the dual impacts of the cleft composition, and further applies the framework of superstatistics
To investigate the impact of cleft heterogeneity mediated through the setup of a distributed Dglut on the glutamate transient in the cleft, we observe the spatially-averaged temporal profile of glutamate concentration, Cglut(t), in the entire cleft space (Fig 1D) as well as in the local volume (Fig 1E) right above the PSD (Fig 1B), using Eqs (6) and (7)
Summary
The phenomenon of synaptic transmission at central excitatory synapses plays an extremely crucial role in the functioning of the central nervous system. The various microscopic events that occur at the chemical synapses together facilitate the transmission of action potentials from one neuron to the other at the synaptic junctions [1] Among these events, the diffusion of presynaptically-released glutamate in the cleft has a pivotal contribution to the synaptic activity as it crucially regulates the generation of excitatory postsynaptic currents (EPSCs) [2,3,4]. Experimental observations regarding the cleft morphology suggest that, rather than having a perfectly regular geometry, the cleft space possesses numerous sudden geometrical irregularities [11, 12] These features directly and constantly hinder the entire passage of a diffusing glutamate molecule across the cleft space. The resulting extrasynaptic geometrical tortousity slows down the glutamate diffusion within the cleft space in a feedback manner [4, 6, 13, 14]
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