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Realistic modelling of receptor activation in hippocampal excitatory synapses: analysis of multivesicular release, release location, temperature and synaptic cross-talk

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Abstract

Chemically mediated synaptic transmission results from fusion of synaptic vesicles with the presynaptic plasma membrane, subsequent release of the vesicular content into the cleft and binding to postsynaptic receptors. Previous modelling studies of excitatory neurotransmitter glutamate were based on simplified geometries failing to account for the biologically realistic synaptic environment, in particular, the presence of astrocytes, the geometry of extracellular space, and the neurotransmitter uptake mechanism. Using 3-dimensional reconstructions of hippocampal glutamatergic synapses including the surrounding astrocytic processes we have developed a biologically realistic model to analyse receptor activation in different conditions. We used the finite element method to simulate glutamate release, analyse glutamate diffusion following single and multiple vesicle release and binding at the postsynaptic site to AMPA and NMDA receptors. We demonstrate that: (1) the transmitter diffusion is highly temperature-sensitive; (2) release conditions and geometry more specifically affect AMPARs than NMDARs; (3) the sensitivities of AMPARs and NMDARs to simultaneous vesicular release are different; (4) in the case of multivesicle neurotransmitter release with variable delays, the binding of glutamate to AMPARs is additive up to 1 ms after the release, then becomes independent, but to NMDARs the binding is additive up to 33 ms; (5) the number of AMPARs varies more than the number of NMDRs in response to the input firing patterns; (6) the presence of astrocytes effectively blocks synaptic cross-talk; and (7) synaptic cross-talk, mediated by NMDARs but not AMPARs, is only possible after quasi-simultaneous multivesicular release at physiological temperature (35°C) without intervening astrocytes, but not at 25°C. Our simulations demonstrate the importance of temperature and ultrastructural synaptic environment in synaptic transmission and synaptic cross-talk.

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Acknowledgments

The authors are grateful to Dr. Paul Tiesinga for critical reading of the manuscript. This work was sponsored by Human Frontier Science Program (RGY-0073/2006); Canadian Institutes of Health Research (MOP-81105); National Science and Engineering Research Council of Canada (NSERC-8687-05).

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  1. Centre de Recherche Université Laval Robert-Giffard, Québec, Canada

    Jérôme Boucher & Attila Sík

  2. Département de Physique, Université Laval, Québec, Canada

    Jérôme Boucher & Helmut Kröger

  3. School of Clinical and Experimental Medicine, Neuronal Networks Group, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK

    Attila Sík

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  1. Jérôme Boucher
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Boucher, J., Kröger, H. & Sík, A. Realistic modelling of receptor activation in hippocampal excitatory synapses: analysis of multivesicular release, release location, temperature and synaptic cross-talk. Brain Struct Funct 215, 49–65 (2010). https://doi.org/10.1007/s00429-010-0273-x

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