Skip to main content
SpringerLink
Log in

Saturation in excitatory synapses of hippocampus investigated by computer simulations

  • Published:
Biological Cybernetics Aims and scope Submit manuscript

Abstract.

The standard view of the synaptic function in excitatory synapses has been deeply questioned by recent experimental data on hippocampal glutamate synapses both for possible receptor nonsaturation and for larger and non-Gaussian peak amplitude fluctuations. Our previous investigations of the mechanisms involved in the variability of the response of hippocampal glutamatergic synapses, carried out by computer simulation of simple Brownian models of glutamate diffusion, furnished initial evidence about their presynaptic character. A new, refined model, reported here, assumes a collision volume for the glutamate molecule and a more realistic description of receptors and their binding dynamics. Based on this model, conditions for AMPA and NMDA receptor saturation have been investigated and new miniature (or quantal) EPSC parameters have been computed. The results corroborate the hypothesis that the lack of AMPA and NMDA receptor saturation and the EPSC stochastic variability are attributable to the small volume of glutamatergic synaptic vesicles and hence to the small number of glutamate molecules diffusing in the cleft after a vesicle release. The investigations better characterize some not well-known elements of the synaptic structure, such as the fusion pore, and provide useful information on AMPA receptor dynamics. Indeed, a nice fit between computed EPSCs and some miniature EPSCs in recent experimental literature allowed for the computation of new transition time values among the different AMPA receptor states through a trial-and-error optimization procedure. Moreover, the model has been used to evaluate two hypotheses on the genesis of the long-term potentiation phenomenon.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Agmon N, Edelstein AL (1997) Collective binding properties of receptor arrays. Biophys J 72: 1582–1594

    Google Scholar 

  2. Armstrong N, Gouaux E (2000) Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core. Neuron 28: 165–181

    Google Scholar 

  3. Armstrong N, Sun Y, Chen GQ, Gouaux E (1998) Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 395: 913–917

    Google Scholar 

  4. Auger C, Marty A (2000) Quantal currents at single-site central synapses. J Physiol 526: 3–11

    Google Scholar 

  5. Bartol TM Jr, Land BR, Salpeter EE, Salpeter MM (1991) Monte Carlo simulation of miniature endplate current generation in the vertebrate neuromuscular junction. Biophys J 59: 1290–1307

    Google Scholar 

  6. Bekkers JM, Richerson GB, Stevens CF (1990) Origin of variability in quantal size in cultured hippocampal neurons and hippocampal slices. Proc Natl Acad Sci USA 87: 5359–5362

    Google Scholar 

  7. Bruns D, Jahn R (1995) Real-time measurement of transmitter release from single synaptic vesicles. Nature 377: 62–65

    Google Scholar 

  8. Clements JD (1996) Transmitter timecourse in the synaptic cleft: its role in central synaptic function. Trends Neurosci 19: 163–171

    Google Scholar 

  9. Clements JD, Lester RA, Tong J, Jahr CE, Westbrook GL (1992) The time course of glutamate in the synaptic cleft. Science 258: 11498–11501

    Google Scholar 

  10. Colquhoun D, Jonas P, Sakmann B (1992) Action of brief pulses of glutamate on AMPA/kainate receptors in patches from different neurons of rat hippocampal slices. J Physiol Lond 458: 261–287

    Google Scholar 

  11. Diamond JS, Jahr CE (1997) Transporters buffer synaptically released glutamate on a submillisecond time scale. J Neurosci 17: 4672–4687

    Google Scholar 

  12. Edelstein AL, Agmon N (1997) Brownian simulation of many-particle binding to a reversible receptor array. J Comput Phys 132: 260–275

    Google Scholar 

  13. Forti L, Bossi M, Bergamaschi A, Villa A, Malgaroli A (1997) Loose-patch recordings of single quanta at individual hippocampal synapses. Nature 388: 874–878

    Google Scholar 

  14. Gegelashvili G, Dehnes Y, Danbolt NC, Schousboe A (2000) The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms. Neurochem Int 37: 163–170

    Google Scholar 

  15. Gillespie DT (1996) The mathematics of Brownian motion and Johnson noise. Am J Phys 64: 225–240

    Google Scholar 

  16. Glavinovic MI (1999) Monte carlo simulation of vesicular release, spatiotemporal distribution of glutamate in synaptic cleft and generation of postsynaptic currents. Pflugers Arch 437: 462–470

    Google Scholar 

  17. Hanse E, Gustafsson B (2001) Quantal variability at glutamatergic synapses in area CA1 of the rat neonatal hippocampus. J Physiol 531: 467–480

    Google Scholar 

  18. Holmes WR (1995) Modeling the effect of glutamate diffusion and uptake on NMDA and non-NMDA receptor saturation. Biophys J 69: 1734–1747

    Google Scholar 

  19. Jahn K, Bufler J, Franke C (1998) Kinetics of AMPA-type glutamate receptor channels in rat caudate-putamen neurons show a wide range of desensitization but distinct recovery characteristics. Eur J Neurosci 10: 664–672

    Google Scholar 

  20. Jayaraman V, Keesey R, Madden DR (2000) Ligand–protein interactions in the glutamate receptor. Biochemistry 39: 8693–8697

    Google Scholar 

  21. Jonas P, Major G, Sakmann B (1993) Quantal components of unitary EPSCs at the mossy fibre synapse on CA3 pyramidal cells of rat hippocampus. J Physiol Lond 472 C: 615–663

    Google Scholar 

  22. Jonas P, Spruston N (1994) Mechanisms shaping glutamate-mediated excitatory postsynaptic currents in the CNS. Curr Opin Neurobiol 4: 366–372

    Google Scholar 

  23. Kleinle J, Vogt K, Luscher HR, Muller L, Senn W, Wyler K, Streit J (1996) Transmitter concentration profiles in the synaptic cleft: an analytical model of release and diffusion. Biophys J 71: 2413–2426

    Google Scholar 

  24. Kruk PJ, Korn H, Faber DS (1997) The effects of geometrical parameters on synaptic transmission: a Monte Carlo simulation study. Biophys J 73: 2874–2890

    Google Scholar 

  25. Kullmann DM (2003) Silent synapses: what are they telling us about long-term potentiation? Philos Trans R Soc Lond B Biol Sci 358: 727–733

    Google Scholar 

  26. Liu G (2003) Presynaptic control of quantal size: kinetic mechanisms and implications for synaptic transmission and plasticity. Curr Opin Neurobiol 13: 324–331

    Google Scholar 

  27. Liu G, Choi S, Tsien RW (1999) Variability of neurotransmitter concentration and nonsaturation of postsynaptic AMPA receptor at synapses in hippocampal cultures and slices. Neuron 22: 395–409

    Google Scholar 

  28. Longsworth LG (1953) Diffusion measurements at 25° of aqueous solutions of amino acids, peptides and sugars. J Am Chem Soc 75: 5705–5709

    Google Scholar 

  29. Mainen ZF, Malinow R, Svoboda K (1999) Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated. Nature 399: 151–155

    Google Scholar 

  30. McAllister AK, Stevens CF (2000) Nonsaturation of AMPA and NMDA receptors at hippocampal synapses. Proc Natl Acad Sci USA 97: 6173–6178

    Google Scholar 

  31. Montgomery JM, Pavlidis P, Madison DV (2001) Pair recordings reveal all-silent synaptic connections and the postsynaptic expression of long-term potentiation. Neuron 29: 691–701

    Google Scholar 

  32. Murphy TH, Baraban JM, Wier WG (1995) Mapping miniature synaptic currents to single synapses using calcium imaging reveals heterogeneity in postsynaptic output. Neuron 15: 159–168

    Google Scholar 

  33. Paas Y, Devillers-Thiery A, Teichberg VI, Changeux JP, Eisenstein M (2000) How well can molecular modelling predict the crystal structure: the case of the ligand-binding domain of glutamate receptors. Trends Pharmacol Sci 21: 87–92

    Google Scholar 

  34. Palfrey HC, Artalejo CR (2003) Secretion: kiss and run caught on film. Curr Biol 13: R397–399

    Google Scholar 

  35. Poncer JC, Malinow R (2001) Postsynaptic conversion of silent synapses during LTP affects synaptic gain and transmission dynamics. Nat Neurosci 4: 989–996

    Google Scholar 

  36. Reigada D, Diez-Perez I, Gorostiza P, Verdaguer A, Gomez de Aranda I, Pineda O, Vilarrasa J, Marsal J, Blasi J, Aleu J, Solsona C (2003) Control of neurotransmitter release by an internal gel matrix in synaptic vesicles. Proc Natl Acad Sci USA 100: 3485–3490

    Google Scholar 

  37. Rusakov DA, Kullmann DM (1998) Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural constraints, uptake, and receptor activation. J Neurosci 18: 3158–3170

    Google Scholar 

  38. Schikorski T, Stevens CF (1997) Quantitative ultrastructural analysis of hippocampus excitatory synapses. J Neurosci 17: 5858–5867

    Google Scholar 

  39. Shupliakov O, Brodin L, Cullheim S, Ottersen OP, Storm-Mathisen J (1992) Immunogold quantification of glutamate in two types of excitatory synapse with different firing patterns. J Neurosci 12: 3789–3803

    Google Scholar 

  40. Stevens CF, Wang Y (1994) Changes in reliability of synaptic function as a mechanism for plasticity. Nature 371: 704–707

    Google Scholar 

  41. Stevens CF, Williams JH (2000) ‘‘Kiss and run’’ exocytosis at hippocampal synapses. Proc Natl Acad Sci USA 97: 12828–12833

    Google Scholar 

  42. Trommershauser J, Marienhagen J, Zippelius A (1999) Stochastic model of central synapses: slow diffusion of transmitter interacting with spatially distributed receptors and transporters. J Theor Biol 198: 101–120

    Google Scholar 

  43. Umemiya M, Senda M, Murphy TH (1999) Behaviour of NMDA and AMPA receptor-mediated miniature EPSCs at rat cortical neuron synapses identified by calcium imaging. J Physiol Lond 521(Pt 1): 113–122

    Google Scholar 

  44. Uteshev VV, Pennefather PS (1996) A mathematical description of miniature postsynaptic current generation at central nervous system synapses. Biophys J 71: 1256–1266

    Google Scholar 

  45. Ventriglia F, Di Maio V (2000a) A Brownian simulation model of glutamate synaptic diffusion in the femtosecond time scale. Biol Cybern 83: 93–109

    Google Scholar 

  46. Ventriglia F, Di Maio V (2000b) A Brownian model of glutamate diffusion in excitatory synapses of Hippocampus. Biosystems 58: 67–74

    Google Scholar 

  47. Ventriglia F, Di Maio V (2002) Stochastic fluctuations of the synaptic function. Biosystems 67: 287–294

    Google Scholar 

  48. Ventriglia F, Di Maio V (2003a) Synaptic fusion pore structure and AMPA receptor activation according to Brownian simulation of glutamate diffusion. Biol Cybern 88: 201–209

    Google Scholar 

  49. Ventriglia F, Di Maio V (2003b) Stochastic fluctuations of the quantal EPSC amplitude in computer simulated excitatory synapses of hippocampus. Biosystems 71: 195–204

    Google Scholar 

  50. Ventriglia F, Di Maio V, Talamo O (1999) A model of synaptic diffusion by brownian simulation. In: Abstracts of the workshop on neural coding, 11–15 October 1999, Osaka, Japan, pp 5–7

  51. Wahl LM, Pouzat C, Stratford KJ (1996) Monte Carlo simulation of fast excitatory synaptic transmission at a hippocampal synapse. J Neurophysiol 75: 597–608

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Istituto di Cibernetica, “E. Caianiello” del CNR, Via Campi Flegrei 34, 80078, Pozzuoli (NA), Italy

    Francesco Ventriglia

Authors
  1. Francesco Ventriglia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Ventriglia.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ventriglia, F. Saturation in excitatory synapses of hippocampus investigated by computer simulations. Biol. Cybern. 90, 349–359 (2004). https://doi.org/10.1007/s00422-004-0476-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00422-004-0476-4

Keywords

Search

Navigation