Extrasynaptic Glutamate Diffusion in the Hippocampus: Ultrastructural Constraints, Uptake, and Receptor Activation
Open accessAbstract
Fast excitatory synapses are generally thought to act as private communication channels between presynaptic and postsynaptic neurons. Some recent findings, however, suggest that glutamate may diffuse out of the synaptic cleft and bind to several subtypes of receptors, either in the perisynaptic membrane or at neighboring synapses. It is not known whether activation of these receptors can occur in response to the release of a single vesicle of glutamate. Here we estimate the spatiotemporal profile of glutamate in the extrasynaptic space after vesicle exocytosis, guided by detailed ultrastructural measurements of the CA1 neuropil in the adult rat. We argue that the vicinity of the synapse can be treated as an isotropic porous medium, in which diffusion is determined by the extracellular volume fraction and the tortuosity factor, and develop novel stereological methods to estimate these parameters. We also estimate the spatial separation between synapses, to ask whether glutamate released at one synapse can activate NMDA and other high-affinity receptors at a neighboring synapse. Kinetic simulations of extrasynaptic glutamate uptake show that transporters rapidly reduce the free concentration of transmitter. Exocytosis of a single vesicle is, however, sufficient to bind to high-affinity receptors situated in the immediate perisynaptic space. The distance separating a typical synapse from its nearest neighbor is ∼465 nm. Whether glutamate can reach a sufficient concentration to activate NMDA receptors at this distance depends critically on the diffusion coefficient in the extracellular space. If diffusion is much slower than in free aqueous solution, NMDA receptors could mediate crosstalk between neighboring synapses.
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Two-photon excitation of MNI-glutamate permits functional mapping of glutamate sensitivity with a spatiotemporal resolution similar to that achieved by activation of presynaptic terminals (~0.4 μm and ~0.1 ms).
“Nevertheless, two-photon excitation of MNI-glutamate permits the functional mapping of glutamate sensitivity with a spatiotemporal resolution similar to that achieved by activation of presynaptic terminals (~0.4μm and ~0.1 ms)28.”
From Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons (2001) · cites this paper as [28]
The Synaptic currents and Activation of extrasynaptic receptors sections discuss modeled glutamate diffusion and receptor activation at distances around 400–465 nm; they do not describe the resolution of functional mapping. Searches for MNI-glutamate, two-photon excitation, and the claimed 0.1 ms resolution found no passage addressing the comparison with presynaptic-terminal activation. Page numbers were not available in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThin spines and filopodia may be postsynaptic components of silent synapses.
“In addition, our study suggests that thin spines and filopodia may be postsynaptic components of silent synapses28, 32, 34, 44.”
From Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons (2001) · cites this paper as [28]
The Activation of extrasynaptic receptors section discusses NMDA-receptor activation at neighboring synapses and notes that dendritic spines may change shape, but does not identify thin spines or filopodia as components of silent synapses. Searches for “filopodia,” “thin spines,” and “silent synapses” found no passage making that connection; silent synapses appear in the References. (LLM, conf=0.74)
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- Authors
- Rusakov, D. A., & Kullmann, D. M.
- Affiliations
- The Open University (GB)
- UCL Queen Square Institute of Neurology (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1998-05-01
- Volume
- 18
- Issue
- 9
- Pages
- 3158-3170
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6792642
- OpenAlex
- W1897919376
- Cited by
- 438
- References
- 1
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 9 · 2023: 14 · 2022: 11 · 2021: 16 · 2020: 15 · 2019: 12 · 2018: 9 · 2017: 12 · 2016: 15 · 2015: 10 · 2014: 15 · 2013: 17 · 2012: 15
- FWCI
- 10.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Directorate for Biological Sciences
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- hippocampal CA1, NMDA receptor, glutamate transporters, stereology, tortuosity, extracellular volume fraction, ultrastructure
- MeSH terms
- Animals, Cell Membrane, Computer Simulation, Diffusion, Hippocampus, Male, Surface Properties, Synapses, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Receptors, AMPA, Glutamic Acid, Neuropil, Rats
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