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Synaptic cleft geometry modulates NMDAR opening probability by tuning neurotransmitter residence time
María Hernández Mesa1, Kimberly J McCabe2, Padmini Rangamani3
1Department of Computational Physiology, Simula Research Laboratory, 0164 Oslo, Norway; Department of Informatics, University of Oslo, 0373 Oslo, Norway.
Biophysical Journal
|January 29, 2025
Summary
Synaptic geometry significantly impacts neurotransmitter receptor activation. Specific shapes like curved or nonparallel membranes enhance N-methyl-D-aspartate receptor (NMDAR) function, while NMDAR clustering further boosts activation.
Area of Science:
- Neuroscience
- Computational Biology
- Biophysics
Background:
- Synaptic morphology influences neurotransmitter diffusion and receptor dynamics.
- Key geometric factors include synaptic cleft curvature, membrane distance, and surface-area-to-volume ratio.
- These factors critically affect glutamate diffusion and N-methyl-D-aspartate receptor (NMDAR) activation.
Purpose of the Study:
- To develop a stochastic model for receptor activation using realistic synaptic geometries.
- To investigate the impact of biophysical properties and idealized cleft geometries on receptor activation.
- To elucidate how synaptic structure modulates neurotransmission and synaptic plasticity.
Main Methods:
- Developed a stochastic model for N-methyl-D-aspartate receptor (NMDAR) activation.
- Simulated receptor activation using realistic and idealized synaptic geometries.
- Analyzed the effects of synaptic cleft curvature, membrane configuration, and NMDAR clustering.
Main Results:
- Synaptic structure significantly impacts NMDAR activation variability.
- Increased membrane curvature can compensate for wider synaptic clefts.
- Nonparallel membranes and NMDAR clustering enhance activation by increasing glutamate residence time.
Conclusions:
- Synaptic geometry is a critical determinant of neurotransmitter receptor activation.
- Structural modifications, including membrane shape and receptor clustering, can fine-tune synaptic efficacy.
- This study provides insights into the regulation of neurotransmission and synaptic plasticity through physical structure.
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