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Modeling spontaneous and evoked glutamate release of NMDA receptors
BMC Neuroscience volume 10, Article number: P217 (2009)
Spontaneous synaptic fusion is a feature in all synapses. These random release events have been extremely instrumental in the analysis of unitary properties of neurotransmission. Here, we detail some modeling studies for the kinetic scheme of NMDA receptors in a synapse that was published in . In a synapse, spontaneous and action-potential-driven neurotransmitter release is assumed to activate the same set of postsynaptic receptors. However, new experiments using MK-801, a well characterized use-dependent blocker of NMDA receptors shows NMDA-receptor-mediated spontaneous miniature EPSCs (NMDA-mEPSCs) and NMDA-receptor-mediated evoked EPSCs (NMDA-eEPSCs) responded with very different characters . Modeling glutamate diffusion and NMDA receptor activation revealed that postsynaptic densities larger than ≈0.2 μm2 can accommodate two populations of NMDA receptors with primarily nonoverlapping responsiveness. Collectively, these results support the premise that spontaneous and evoked neurotransmissions activate distinct sets of NMDA receptors and signal independently to the postsynaptic side.
This model can recapitulate several key features (including the asymmetry in the extent of cross talk detected after MK-801 block of NMDA-mEPSCs vs NMDA-eEPSCs) with the assumption that within a 0.36 μm2 PSD, a release event near the center (e.g., the vicinity of R6) represents evoked neurotransmission, whereas a fusion event at the periphery of the PSD (e.g., near R16) corresponds to spontaneous release. Moreover, in the Figure, this model indicates that experimental findings  are in line with the commonly accepted parameters governing glutamate diffusion in synapses (Xu-Friedman and Regehr ; Popescu et al., 2004 ). According to this model, medium to large (>0.2 μm2 area) synapses can easily accommodate independent signaling via spontaneous and evoked release with some geometric constraints.
Atasoy D, Ertunc M, Moulder KL, Blackwell J, Chung CH, Su J, Kavalali ET: Spontaneous and evoked glutamate release activates two populations of NMDA receptors with limited overlap. J Neurosci. 2008, 28: 10151-10166. 10.1523/JNEUROSCI.2432-08.2008.
Xu-Friedman MA, Regehr WG: Ultrastructural contributions to desensitization at cerebellar mossy fiber to granule cell synapses. J Neurosci. 2003, 23: 2182-2192.
Popescu G, Robert A, Howe JR, Auerbach A: Reaction mechanism determines NMDA receptor response to repetitive stimulation. Nature. 2004, 430: 790-793. 10.1038/nature02775.
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Su, J., Blackwell, J. & Kavalali, E.T. Modeling spontaneous and evoked glutamate release of NMDA receptors. BMC Neurosci 10, P217 (2009). https://doi.org/10.1186/1471-2202-10-S1-P217
- NMDA Receptor
- Glutamate Release
- Geometric Constraint
- Kinetic Scheme
- Release Event