Synaptic cleft geometry modulates NMDAR opening probability by tuning neurotransmitter residence time

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Synaptic morphology plays a critical role in modulating the dynamics of neurotransmitter diffusion and receptor activation in interneuron communication. In this study, we investigated how variations in synaptic geometry, including curvature of the synaptic cleft, distance between the presynaptic and postsynaptic membranes, and the surface area-to-volume ratio of the cleft, influence glutamate diffusion and N-Methyl-D-Aspartate receptor (NMDAR) opening probabilities. We developed a stochastic model for receptor activation using reconstructions from realistic synaptic geometries. Our simulations revealed a substantial variability in NMDAR activation, highlighting the significant impact of synaptic structure on receptor dynamics. By exploring the interplay between curvature and surface area-to-volume ratio, we found that increasing the curvature of the synaptic membranes could compensate for reduced NMDAR activation when the synaptic cleft distance was large. We also found that non-parallel membrane configurations, particularly convex presynapses or concave postsynaptic densities (PSDs), maximize NMDAR activation via increased surface area-to-volume ratio, leading to prolonged glutamate residence and reduced leakage. Finally, introducing NMDAR clustering within the PSD significantly enhanced receptor activation across different geometric conditions and mitigated the effects of synaptic morphology on NMDAR opening probabilities. Our findings underscore the complex interplay between synaptic geometry and receptor dynamics, providing insights into how structural modifications can influence synaptic efficacy and plasticity.

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Significance statement

This study demonstrates that synaptic morphology profoundly shapes neurotransmitter diffusion and NMDA receptor activation, directly impacting synaptic efficacy. Our model shows that factors like synaptic cleft curvature, membrane spacing, and surface area-to-volume ratio significantly influence receptor dynamics. Given the dynamic nature of dendritic spines, which change shape and size during synaptic plasticity, our findings illustrate how purely morphological changes in cleft structure can modulate interneuronal communication and signal strength.