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Brain Structure and Function
Published in: Brain Structure and Function 1/2010

01-07-2010 | Original article

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

Authors: Jérôme Boucher, Helmut Kröger, Attila Sík

Published in: Brain Structure and Function | Issue 1/2010

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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.
Literature
Agmon N, Edelstein AL (1997) Collective binding properties of receptor arrays. Biophys J 72:1582–1594CrossRefPubMed
Andrasfalvy BK, Magee JC (2001) Distance-dependent increase in AMPA receptor number in the dendrites of adult hippocampal CA1 pyramidal neurons. J Neurosci 21:9151–9159PubMed
Asztely F, Erdemli G, Kullmann DM (1997) Extrasynaptic glutamate spillover in the hippocampus: dependence on temperature and the role of active glutamate uptake. Neuron 18:281–293CrossRefPubMed
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 59:1290–1307CrossRefPubMed
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 87:5359–5362CrossRefPubMed
Bergles DE, Jahr CE (1998) Glial contribution to glutamate uptake at Schaffer collateral-commissural synapses in the hippocampus. J Neurosci 18:7709–7716PubMed
Chen KC, Nicholson C (2000) Changes in brain cell shape create residual extracellular space volume and explain tortuosity behavior during osmotic challenge. Proc Natl Acad Sci USA 97:8306–8311CrossRefPubMed
Clements JD (1996) Transmitter timecourse in the synaptic cleft: its role in central synaptic function. Trends Neurosci 19:163–171CrossRefPubMed
Clements JD, Lester RA, Tong G, Jahr CE, Westbrook GL (1992) The time course of glutamate in the synaptic cleft. Science 258:1498–1501CrossRefPubMed
De Robertis E (1967) Ultrastructure and cytochemistry of the synaptic region. The macromolecular components involved in nerve transmission are being studied. Science 156:907–914CrossRefPubMed
Diamond JS, Jahr CE (1997) Transporters buffer synaptically released glutamate on a submillisecond time scale. J Neurosci 17:4672–4687PubMed
Dobrunz LE, Stevens CF (1997) Heterogeneity of release probability, facilitation, and depletion at central synapses. Neuron 18:995–1008CrossRefPubMed
Faber DS, Young WS, Legendre P, Korn H (1992) Intrinsic quantal variability due to stochastic properties of receptor–transmitter interactions. Science 258:1494–1498CrossRefPubMed
Forti L, Bossi M, Bergamaschi A, Villa A, Malgaroli A (1997) Loose-patch recordings of single quanta at individual hippocampal synapses. Nature 388:874–878CrossRefPubMed
Franks KM, Bartol TM Jr, Sejnowski TJ (2002) A Monte Carlo model reveals independent signaling at central glutamatergic synapses. Biophys J 83:2333–2348CrossRefPubMed
Franks KM, Stevens CF, Sejnowski TJ (2003) Independent sources of quantal variability at single glutamatergic synapses. J Neurosci 23:3186–3195PubMed
Frerking M, Borges S, Wilson M (1995) Variation in GABA mini amplitude is the consequence of variation in transmitter concentration. Neuron 15:885–895CrossRefPubMed
Geiger JRP, Roth A, Tasskin B, Jonas P (1999) Glutamate-mediated synaptic excitation of cortical interneurons. In: The handbook of experimental pharmacology. Springer, Berlin
Glavinovic MI, Rabie HR (1998) Monte Carlo simulation of spontaneous miniature excitatory postsynaptic currents in rat hippocampal synapse in the presence and absence of desensitization. Pflugers Arch 435:193–202CrossRefPubMed
Hanse E, Gustafsson B (2001a) Quantal variability at glutamatergic synapses in area CA1 of the rat neonatal hippocampus. J Physiol 531:467–480CrossRefPubMed
Hanse E, Gustafsson B (2001b) Vesicle release probability and pre-primed pool at glutamatergic synapses in area CA1 of the rat neonatal hippocampus. J Physiol 531:481–493CrossRefPubMed
Harris KM, Landis DM (1986) Membrane structure at synaptic junctions in area CA1 of the rat hippocampus. Neuroscience 19:857–872CrossRefPubMed
Hestrin S, Nicoll RA, Perkel DJ, Sah P (1990a) Analysis of excitatory synaptic action in pyramidal cells using whole-cell recording from rat hippocampal slices. J Physiol 422:203–225PubMed
Hestrin S, Sah P, Nicoll RA (1990b) Mechanisms generating the time course of dual component excitatory synaptic currents recorded in hippocampal slices. Neuron 5:247–253CrossRefPubMed
Heuser JE, Reese TS, Dennis MJ, Jan Y, Jan L, Evans L (1979) Synaptic vesicle exocytosis captured by quick freezing and correlated with quantal transmitter release. J Cell Biol 81:275–300CrossRefPubMed
Holmes WR (1995) Modeling the effect of glutamate diffusion and uptake on NMDA and non-NMDA receptor saturation. Biophys J 69:1734–1747CrossRefPubMed
Isaac JT, Oliet SH, Hjelmstad GO, Nicoll RA, Malenka RC (1996) Expression mechanisms of long-term potentiation in the hippocampus. J Physiol Paris 90:299–303CrossRefPubMed
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 472:615–663PubMed
Katz B (1969) The release of neural transmitter substances. Liverpool University Press, Liverpool, UK
Kharazia VN, Weinberg RJ (1999) Immunogold localization of AMPA and NMDA receptors in somatic sensory cortex of albino rat. J Comp Neurol 412:292–302CrossRefPubMed
Kidd FL, Isaac JT (2001) Kinetics and activation of postsynaptic kainate receptors at thalamocortical synapses: role of glutamate clearance. J Neurophysiol 86:1139–1148PubMed
Kirov SA, Sorra KE, Harris KM (1999) Slices have more synapses than perfusion-fixed hippocampus from both young and mature rats. J Neurosci 19:2876–2886PubMed
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 71:2413–2426CrossRefPubMed
Korn H, Bausela F, Charpier S, Faber DS (1993) Synaptic noise and multiquantal release at dendritic synapses. J Neurophysiol 70:1249–1254PubMed
Kruk PJ, Korn H, Faber DS (1997) The effects of geometrical parameters on synaptic transmission: a Monte Carlo simulation study. Biophys J 73:2874–2890CrossRefPubMed
Kullmann DM, Asztely F (1998) Extrasynaptic glutamate spillover in the hippocampus: evidence and implications. Trends Neurosci 21:8–14CrossRefPubMed
Kullmann DM, Siegelbaum SA (1995) The site of expression of NMDA receptor-dependent LTP: new fuel for an old fire. Neuron 15:997–1002CrossRefPubMed
Kullmann DM, Erdemil G, Asztely F (1996) LTP of AMPA and NMDA receptor-mediated signals: evidence for presynaptic expression and extrasynaptic glutamate spill-over. Neuron 17:461–474CrossRefPubMed
Lehre KP, Danbolt NC (1998) The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci 18:8751–8757PubMed
Lester RA, Jahr CE (1992) NMDA channel behavior depends on agonist affinity. J Neurosci 12:635–643PubMed
Liu G, Tsien RW (1995) Synaptic transmission at single visualized hippocampal boutons. Neuropharmacology 34:1407–1421CrossRefPubMed
Liu G, Choi S, Tsien RW (1999) Variability of neurotransmitter concentration and nonsaturation of postsynaptic AMPA receptors at synapses in hippocampal cultures and slices. Neuron 22:395–409CrossRefPubMed
Longsworth LG (1953) Diffusion measurements, at 25, of aqueous solutions of amino acids, peptides and sugars. J Am Chem Soc 75:5705–5709
Magleby KL, Stevens CF (1972) A quantitative description of end-plate currents. J Physiol 223:173–197PubMed
Mainen ZF, Malinow R, Svoboda K (1999) Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated. Nature 399:151–155CrossRefPubMed
Matsuzaki M, Ellis-Davies GC, Nemoto T, Miyashita Y, Iino M, Kasai H (2001) Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat Neurosci 4:1086–1092CrossRefPubMed
McAllister AK, Stevens CF (2000) Nonsaturation of AMPA and NMDA receptors at hippocampal synapses. Proc Natl Acad Sci USA 97:6173–6178CrossRefPubMed
Murthy VN, Schikorski T, Stevens CF, Zhu Y (2001) Inactivity produces increases in neurotransmitter release and synapse size. Neuron 32:673–682CrossRefPubMed
Nieto-Sampedro M, Hoff SF, Cotman CW (1982) Perforated postsynaptic densities: probable intermediates in synapse turnover. Proc Natl Acad Sci USA 79:5718–5722CrossRefPubMed
Nusser Z, Lujan R, Laube G, Roberts JD, Molnar E, Somogyi P (1998) Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron 21:545–559CrossRefPubMed
Patneau DK, Mayer ML (1990) Structure-activity relationships for amino acid transmitter candidates acting at N-methyl-d-aspartate and quisqualate receptors. J Neurosci 10:2385–2399PubMed
Peters A, Palade SL, Webster HDF (1991) The fine structure of the nervous system. Oxford University Press, New York
Prange O, Murphy TH (1999) Analysis of multiquantal transmitter release from single cultured cortical neuron terminals. J Neurophysiol 81:1810–1817PubMed
Raastad M, Storm JF, Andersen P (1992) Putative single quantum and single fibre excitatory postsynaptic currents show similar amplitude range and variability in rat hippocampal slices. Eur J Neurosci 4:113–117CrossRefPubMed
Racca C, Stephenson FA, Streit P, Roberts JD, Somogyi P (2000) NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area. J Neurosci 20:2512–2522PubMed
Raghavachari S, Lisman JE (2004) Properties of quantal transmission at CA1 synapses. J Neurophysiol 92:2456–2467CrossRefPubMed
Rusakov DA, Kullmann DM (1998) A tortuous and viscous route to understanding diffusion in the brain. Trends Neurosci 21:469–470CrossRefPubMed
Rusakov DA, Kullmann DM, Stewart MG (1999) Hippocampal synapses: do they talk to their neighbours? Trends Neurosci 22:382–388CrossRefPubMed
Schikorski T, Stevens CF (1997) Quantitative ultrastructural analysis of hippocampal excitatory synapses. J Neurosci 17:5858–5867PubMed
Schikorski T, Stevens CF (2001) Morphological correlates of functionally defined synaptic vesicle populations. Nat Neurosci 4:391–395CrossRefPubMed
Schmitz D, Frerking M, Nicoll RA (2000) Synaptic activation of presynaptic kainate receptors on hippocampal mossy fiber synapses. Neuron 27:327–338CrossRefPubMed
Schwartz EA, Tachibana M (1990) Electrophysiology of glutamate and sodium co-transport in a glial cell of the salamander retina. J Physiol 426:43–80PubMed
Semyanov A, Kullmann DM (2000) Modulation of GABAergic signaling among interneurons by metabotropic glutamate receptors. Neuron 25:663–672CrossRefPubMed
Spruce AE, Breckenridge LJ, Lee AK, Almers W (1990) Properties of the fusion pore that forms during exocytosis of a mast cell secretory vesicle. Neuron 4:643–654CrossRefPubMed
Stevens CF, Wang Y (1995) Facilitation and depression at single central synapses. Neuron 14:795–802CrossRefPubMed
Stiles JR, Van Helden D, Bartol TM Jr, Salpeter EE, Salpeter MM (1996) Miniature endplate current rise times less than 100 microseconds from improved dual recordings can be modeled with passive acetylcholine diffusion from a synaptic vesicle. Proc Natl Acad Sci USA 93:5747–5752CrossRefPubMed
Takuma H, Kwak S, Yoshizawa T, Kanazawa I (1999) Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis. Ann Neurol 46:806–815CrossRefPubMed
Takumi Y, Ramirez-Leon V, Laake P, Rinvik E, Ottersen OP (1999) Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat Neurosci 2:618–624CrossRefPubMed
Tong G, Jahr CE (1994a) Block of glutamate transporters potentiates postsynaptic excitation. Neuron 13:1195–1203CrossRefPubMed
Tong G, Jahr CE (1994b) Multivesicular release from excitatory synapses of cultured hippocampal neurons. Neuron 12:51–59CrossRefPubMed
Van der Kloot W, Molgo J (1994) Quantal acetylcholine release at the vertebrate neuromuscular junction. Physiol Rev 74:899–991PubMed
Ventriglia F, Di Maio V (2002) Stochastic fluctuations of the synaptic function. Biosystems 67:287–294CrossRefPubMed
Ventriglia F, Di Maio V (2003) Stochastic fluctuations of the quantal EPSC amplitude in computer simulated excitatory synapses of hippocampus. Biosystems 71:195–204CrossRefPubMed
Ventriglia F, Maio VD (2003) Synaptic fusion pore structure and AMPA receptor activation according to Brownian simulation of glutamate diffusion. Biol Cybern 88:201–209CrossRefPubMed
Vogt KE, Nicoll RA (1999) Glutamate and gamma-aminobutyric acid mediate a heterosynaptic depression at mossy fiber synapses in the hippocampus. Proc Natl Acad Sci USA 96:1118–1122CrossRefPubMed
Wadiche JI, Jahr CE (2001) Multivesicular release at climbing fiber-Purkinje cell synapses. Neuron 32:301–313CrossRefPubMed
Wadiche JI, Arriza JL, Amara SG, Kavanaugh MP (1995) Kinetics of a human glutamate transporter. Neuron 14:1019–1027CrossRefPubMed
Wahl LM, Pouzat C, Stratford KJ (1996) Monte Carlo simulation of fast excitatory synaptic transmission at a hippocampal synapse. J Neurophysiol 75:597–608PubMed
Wall MJ, Usowicz MM (1998) Development of the quantal properties of evoked and spontaneous synaptic currents at a brain synapse. Nat Neurosci 1:675–682CrossRefPubMed
Wathey JC, Nass MM, Lester HA (1979) Numerical reconstruction of the quantal event at nicotinic synapses. Biophys J 27:145–164CrossRefPubMed
Wong RK, Prince DA (1981) Afterpotential generation in hippocampal pyramidal cells. J Neurophysiol 45:86–97PubMed
Wong RK, Prince DA, Basbaum AI (1979) Intradendritic recordings from hippocampal neurons. Proc Natl Acad Sci USA 76:986–990CrossRefPubMed
Zhang B, Ganetzky B, Bellen HJ, Murthy VN (1999) Tailoring uniform coats for synaptic vesicles during endocytosis. Neuron 23:419–422CrossRefPubMed
Zimmermann H, Denston CR (1977) Separation of synaptic vesicles of different functional states from the cholinergic synapses of the Torpedo electric organ. Neuroscience 2:715–730CrossRefPubMed
Metadata
Title
Realistic modelling of receptor activation in hippocampal excitatory synapses: analysis of multivesicular release, release location, temperature and synaptic cross-talk
Authors
Jérôme Boucher
Helmut Kröger
Attila Sík
Publication date
01-07-2010
Publisher
Springer-Verlag
Published in
Brain Structure and Function / Issue 1/2010
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI
https://doi.org/10.1007/s00429-010-0273-x