Abstract
Chemical synapses enable neurons to communicate rapidly, process and filter signals and to store information. However, studying their functional properties is difficult because synaptic connections typically consist of multiple synaptic contacts that release vesicles stochastically and exhibit time-dependent behavior. Moreover, most central synapses are small and inaccessible to direct measurements. Estimation of synaptic properties from postsynaptic currents or potentials is complicated by the presence of nonuniform release probability and nonuniform quantal properties. The presence of multivesicular release and postsynaptic receptor saturation at some synapses can also complicate the interpretation of quantal parameters. Multiple-probability fluctuation analysis (MPFA; also known as variance-mean analysis) is a method that has been developed for estimating synaptic parameters from the variance and mean amplitude of synaptic responses recorded at different release probabilities. This statistical approach, which incorporates nonuniform synaptic properties, has become widely used for studying synaptic transmission. In this chapter, we describe the statistical models used to extract quantal parameters and discuss their interpretation when applying MPFA.
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Fatt P, Katz B (1952) Spontaneous subthreshold activity at motor nerve endings. J Physiol 117:109–128
del Castillo J, Katz B (1954) Quantal components of the end-plate potential. J Physiol 124:560–573
Fatt P, Katz B (1950) Some observations on biological noise. Nature 166:597–598
De Robertis E, Bennett HS (1955) Some features of the submicroscopic morphology of synapses in frog and earthworm. J Biophys Biochem Cytol 1:47
Katz B (1969) The release of neural transmitter substances. Liverpool University Press, Liverpool
Kuno M (1964) Quantal components of excitatory synaptic potentials in spinal motoneurones. J Physiol 175:81–99
Malinow R, Tsien RW (1990) Presynaptic enhancement shown by whole-cell recordings of long-term potentiation in hippocampal slices. Nature 346:177–180
Bekkers JM, Stevens CF (1990) Presynaptic mechanism for long-term potentiation in the hippocampus. Nature 346:724–729
Larkman A, Stratford K, Jack J (1991) Quantal analysis of excitatory synaptic action and depression in hippocampal slices. Nature 350:344–347
Edwards F (1991) Neurobiology. LTP is a long term problem. Nature 350:271–272
Kullmann DM, Nicoll RA (1992) Long-term potentiation is associated with increases in quantal content and quantal amplitude. Nature 357:240–244
Walmsley B, Edwards FR, Tracey DJ (1988) Nonuniform release probabilities underlie quantal synaptic transmission at a mammalian excitatory central synapse. J Neurophysiol 60:889–908
Rosenmund C, Clements JD, Westbrook GL (1993) Nonuniform probability of glutamate release at a hippocampal synapse. Science 262:754–757
Walmsley B (1995) Interpretation of “quantal” peaks in distributions of evoked synaptic transmission at central synapses. Proc Biol Sci 261:245–250
Sigworth FJ (1980) The variance of sodium current fluctuations at the node of Ranvier. J Physiol 307:97–129
Traynelis SF, Silver RA, Cull-Candy SG (1993) Estimated conductance of glutamate receptor channels activated during EPSCs at the cerebellar mossy fiber-granule cell synapse. Neuron 11:279–289
Silver RA, Cull-Candy SG, Takahashi T (1996) Non-NMDA glutamate receptor occupancy and open probability at a rat cerebellar synapse with single and multiple release sites. J Physiol 494(Pt 1):231–250
Silver RA, Momiyama A, Cull-Candy SG (1998) Locus of frequency-dependent depression identified with multiple-probability fluctuation analysis at rat climbing fibre-Purkinje cell synapses. J Physiol 510(Pt 3):881–902
Reid CA, Clements JD (1999) Postsynaptic expression of long-term potentiation in the rat dentate gyrus demonstrated by variance-mean analysis. J Physiol 518(Pt 1):121–130
Clements JD, Silver RA (2000) Unveiling synaptic plasticity: a new graphical and analytical approach. Trends Neurosci 23:105–113
Clamann HP, Mathis J, Lüscher HR (1989) Variance analysis of excitatory postsynaptic potentials in cat spinal motoneurons during posttetanic potentiation. J Neurophysiol 61:403–416
Sargent PB, Saviane C, Nielsen TA et al (2005) Rapid vesicular release, quantal variability, and spillover contribute to the precision and reliability of transmission at a glomerular synapse. J Neurosci 25:8173–8187
Lanore F, Labrousse VF, Szabo Z et al (2012) Deficits in morphofunctional maturation of hippocampal mossy fiber synapses in a mouse model of intellectual disability. J Neurosci 32:17882–17893
Meyer AC, Neher E, Schneggenburger R (2001) Estimation of quantal size and number of functional active zones at the calyx of held synapse by nonstationary EPSC variance analysis. J Neurosci 21:7889–7900
Saviane C, Silver RA (2006) Fast vesicle reloading and a large pool sustain high bandwidth transmission at a central synapse. Nature 439:983–987
Hallermann S, Fejtova A, Schmidt H et al (2010) Bassoon speeds vesicle reloading at a central excitatory synapse. Neuron 68:710–723
Scheuss V, Neher E (2001) Estimating synaptic parameters from mean, variance, and covariance in trains of synaptic responses. Biophys J 81:1970–1989
Neher E, Sakaba T (2003) Combining deconvolution and fluctuation analysis to determine quantal parameters and release rates. J Neurosci Methods 130:143–157
Oleskevich S, Clements J, Walmsley B (2000) Release probability modulates short-term plasticity at a rat giant terminal. J Physiol 524(Pt 2):513–523
Biró AA, Holderith NB, Nusser Z (2005) Quantal size is independent of the release probability at hippocampal excitatory synapses. J Neurosci 25:223–232
Biró AA, Holderith NB, Nusser Z (2006) Release probability-dependent scaling of the postsynaptic responses at single hippocampal GABAergic synapses. J Neurosci 26:12487–12496
Humeau Y, Doussau F, Popoff MR et al (2007) Fast changes in the functional status of release sites during short-term plasticity: involvement of a frequency-dependent bypass of Rac at Aplysia synapses. J Physiol 583:983–1004
Valera AM, Doussau F, Poulain B et al (2012) Adaptation of granule cell to purkinje cell synapses to high-frequency transmission. J Neurosci 32:3267–3280
Sola E, Prestori F, Rossi P et al (2004) Increased neurotransmitter release during long-term potentiation at mossy fibre-granule cell synapses in rat cerebellum. J Physiol 557:843–861
Fourcaudot E, Gambino F, Humeau Y et al (2008) cAMP/PKA signaling and RIM1alpha mediate presynaptic LTP in the lateral amygdala. Proc Natl Acad Sci 105:15130–15135
Murthy VN, Sejnowski TJ, Stevens CF (1997) Heterogeneous release properties of visualized individual hippocampal synapses. Neuron 18:599–612
Bekkers JM, Richerson GB, Stevens CF (1990) Origin of variability in quantal size in cultured hippocampal neurons and hippocampal slices. Proc Natl Acad Sci 87:5359–5362
Silver RA, Traynelis SF, Cull-Candy SG (1992) Rapid-time-course miniature and evoked excitatory currents at cerebellar synapses in situ. Nature 355:163–166
Frerking M, Wilson M (1996) Effects of variance in mini amplitude on stimulus-evoked release: a comparison of two models. Biophys J 70:2078–2091
Borst JG, Lodder JC, Kits KS (1994) Large amplitude variability of GABAergic IPSCs in melanotrophs from Xenopus laevis: evidence that quantal size differs between synapses. J Neurophysiol 71:639–655
Silver RA (2003) Estimation of nonuniform quantal parameters with multiple-probability fluctuation analysis: theory, application and limitations. J Neurosci Methods 130:127–141
Branco T, Staras K, Darcy KJ et al (2008) Local dendritic activity sets release probability at hippocampal synapses. Neuron 59:475–485
Holderith N, Lörincz A, Katona G et al (2012) Release probability of hippocampal glutamatergic terminals scales with the size of the active zone. Nat Neurosci 15:988–997
Wadiche JI, Jahr CE (2001) Multivesicular release at climbing fiber-Purkinje cell synapses. Neuron 32:301–313
Christie JM, Jahr CE (2006) Multivesicular release at Schaffer collateral-CA1 hippocampal synapses. J Neurosci 26:210–216
Foster KA, Regehr WG (2004) Variance-mean analysis in the presence of a rapid antagonist indicates vesicle depletion underlies depression at the climbing fiber synapse. Neuron 43:119–131
DiGregorio DA, Nusser Z, Silver RA (2002) Spillover of glutamate onto synaptic AMPA receptors enhances fast transmission at a cerebellar synapse. Neuron 35:521–533
Barbour B, Hausser M (1997) Intersynaptic diffusion of neurotransmitter. Trends Neurosci 20:377–384
Sakaba T, Schneggenburger R, Neher E (2002) Estimation of quantal parameters at the calyx of Held synapse. Neurosci Res 44:343–356
Minneci F, Kanichay RT, Silver RA (2012) Estimation of the time course of neurotransmitter release at central synapses from the first latency of postsynaptic currents. J Neurosci Methods 205:49–64
Vere Jones D (1966) Simple stochastic models for the release of quanta of transmitter from a nerve terminal. Aust J Stat 8:53–63
Quastel DM (1997) The binomial model in fluctuation analysis of quantal neurotransmitter release. Biophys J 72:728–753
Wong AYC, Graham BP, Billups B et al (2003) Distinguishing between presynaptic and postsynaptic mechanisms of short-term depression during action potential trains. J Neurosci 23:4868–4877
Spruston N, Jaffe DB, Williams SH et al (1993) Voltage- and space-clamp errors associated with the measurement of electrotonically remote synaptic events. J Neurophysiol 70:781–802
Bar-Yehuda D, Korngreen A (2008) Space-clamp problems when voltage clamping neurons expressing voltage-gated conductances. J Neurophysiol 99:1127–1136
Silver RA, Lubke J, Sakmann B et al (2003) High-probability uniquantal transmission at excitatory synapses in barrel cortex. Science 302:1981–1984
Nyquist H (1928) Certain topics in telegraph transmission theory. Trans AIEE 47:617–644
Saviane C, Silver RA (2006) Errors in the estimation of the variance: implications for multiple-probability fluctuation analysis. J Neurosci Methods 153:250–260
Redman S (1990) Quantal analysis of synaptic potentials in neurons of the central nervous system. Physiol Rev 70:165–198
Stricker C, Field AC, Redman SJ (1996) Statistical analysis of amplitude fluctuations in EPSCs evoked in rat CA1 pyramidal neurones in vitro. J Physiol 490(Pt 2):419–441
Tsodyks M, Pawelzik K, Markram H (1998) Neural networks with dynamic synapses. Neural Comput 10:821–835
Scheuss V, Neher E, Schneggenburger R (2002) Separation of presynaptic and postsynaptic contributions to depression by covariance analysis of successive EPSCs at the calyx of held synapse. J Neurosci 22:728–739
Sakaba T, Neher E (2001) Quantitative relationship between transmitter release and calcium current at the calyx of held synapse. J Neurosci 21:462–476
Saviane C, Silver RA (2007) Estimation of quantal parameters with multiple-probability fluctuation analysis. Methods Mol Biol 403:303–317
Turner DA, West M (1993) Bayesian analysis of mixtures applied to post-synaptic potential fluctuations. J Neurosci Methods 47:1–21
Bhumbra GS, Beato M (2013) Reliable evaluation of the quantal determinants of synaptic efficacy using Bayesian analysis. J Neurophysiol 109:603–620
Oertner TG, Sabatini BL, Nimchinsky EA et al (2002) Facilitation at single synapses probed with optical quantal analysis. Nat Neurosci 5:657–664
Yuste R, Majewska A, Cash SS et al (1999) Mechanisms of calcium influx into hippocampal spines: heterogeneity among spines, coincidence detection by NMDA receptors, and optical quantal analysis. J Neurosci 19:1976–1987
Emptage NJ, Reid CA, Fine A et al (2003) Optical quantal analysis reveals a presynaptic component of LTP at hippocampal Schaffer-associational synapses. Neuron 38:797–804
Sylantyev S, Jensen TP, Ross RA et al (2013) Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc Natl Acad Sci 110:5193–5198
Marvin JS, Borghuis BG, Tian L et al (2013) An optimized fluorescent probe for visualizing glutamate neurotransmission. Nat Methods 10:162–170
Kirkby PA, Srinivas Nadella KMN, Silver RA (2010) A compact acousto-optic lens for 2D and 3D femtosecond based 2-photon microscopy. Opt Express 18:13721–13745
Fernández-Alfonso T, Nadella KMNS, Iacaruso MF et al (2014) Monitoring synaptic and neuronal activity in 3D with synthetic and genetic indicators using a compact acousto-optic lens two-photon microscope. J Neurosci Methods 222:69–81
Rothman JS, Silver RA (2014) Data-driven modeling of synaptic transmission and integration. Prog Mol Biol Transl Sci 123:305–350
Acknowledgements
We thank Antoine Valera for comments on the manuscript. FL is supported by an IEF Marie Curie fellowship (FP7) and RAS holds a Wellcome Trust Principal Research Fellowship and an ERC Advanced Grant.
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Lanore, F., Silver, R.A. (2016). Extracting Quantal Properties of Transmission at Central Synapses. In: Korngreen, A. (eds) Advanced Patch-Clamp Analysis for Neuroscientists. Neuromethods, vol 113. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3411-9_10
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DOI: https://doi.org/10.1007/978-1-4939-3411-9_10
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