Monte Carlo simulation of spontaneous miniature excitatory postsynaptic currents in rat hippocampal synapse in the presence and absence of desensitization

Mi, Glavinovíc; Hr, Rabie

doi:10.1007/s004240050501

Cited by 25 publications

(34 citation statements)

References 26 publications

(48 reference statements)

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“…GluR desensitization is an important mechanism shaping excitatory postsynaptic potentials in the brain (Jones and Westbrook, 1996;Glavinovic and Rabie, 1998). As a gating process, desensitization originates in the ligand-binding domain and propagates to the ion channel.…”

Section: Discussionmentioning

confidence: 99%

Block of AMPA Receptor Desensitization by a Point Mutation outside the Ligand-Binding Domain

Yelshansky¹,

Sobolevsky²,

Jatzke³

et al. 2004

J. Neurosci.

101

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Desensitization of ionotropic glutamate receptors (GluRs), specifically the AMPA receptor subtype, shapes the postsynaptic response at certain synapses in the brain. All known mechanisms that alter desensitization, either pharmacological or mutational, are associated with the ligand-binding domain. Here we report that substitution of a conserved positively charged arginine (R) with a negatively charged glutamate in the linker between the pore-forming M3 segment and the S2 lobe, a region outside the ligand-binding domain, blocks desensitization in homomeric AMPA receptors composed of GluR-B i subunits. A charge-reversing substitution of a glutamate adjacent to this conserved R enhanced desensitization, consistent with these effects attributable to electrostatics. Homologous substitutions of the conserved R in GluR-B o , GluR-A i and the kainate receptor GluR-6 subunits produced comparable but less visible effects on desensitization. Subunit specificity was also apparent for accessibility of substituted cysteines in the M3-S2 linker, suggesting that this part of the channel is not structurally identical in different GluRs. Additionally, reactivity with a sulfhydryl-specific reagent was state dependent, suggesting that the conformations of the nonconducting closed and desensitized states are different at the level of the M3-S2 linker. Our results therefore represent the first identification of elements outside the ligand-binding domain affecting desensitization in non-NMDA receptor channels and suggest that electrostatic interactions involving charged residues in the M3-S2 linker influence channel gating in a subunit-and subtype-specific manner.

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Section: Discussionmentioning

confidence: 99%

Block of AMPA Receptor Desensitization by a Point Mutation outside the Ligand-Binding Domain

Yelshansky¹,

Sobolevsky²,

Jatzke³

et al. 2004

J. Neurosci.

101

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“…where k is the appropriate rate constant (in s -1 ; [17,39]). The 1-µs time step used in all our calculations ensures that the probability of a receptor changing state twice within one time step is <1 in 100.…”

Section: Introductionmentioning

confidence: 99%

“…A receptor can be unbound (C 1 ), in a single-or in a double-bound state (C 2 and C 3 respectively; these are also called activatable states), open (O 4 ), or in one of the three desensitized states (C 5 , C 6 , and C 7 ). As described previously [5,17,39], each state of the receptor is associated with a surface area and a probability of binding, given that a transmitter molecule hits this receptor surface. The inverse of the receptor surface area is the density of the receptor molecules (σ r ) at the postsynaptic membrane.…”

Section: Introductionmentioning

confidence: 99%

“…The random numbers were obtained from a random number generator (MATLAB); D was assumed to be the same as for glutamine (D=760 µm 2 /s at 25°C [27]), but was corrected to 1040 µm 2 /s for a temperature of 37°C in all our calculations (the Q 10 is assumed to be 1.3 [21]). Diffusion in a restricted space is simulated by assuming that the transmitter molecules collide elastically with the walls of the space (vesicle, fusion pore and presynaptic or postsynaptic membranes [17,39]. The kinetic scheme of channel gating is the same as reported by Jonas et al [23] for the mossy fiber synapse on CA3 pyramidal cells of rat hippocampus.…”

Section: Introductionmentioning

confidence: 99%

“…There is very little information about how changes in glutamate concentration in the synaptic cleft interact with presynaptic vesicular release or postsynaptic generation of the postsynaptic current. Several attempts have been made to determine how the concentration of glutamate [4,9,16,17,22,39], and of transmitter generally, changes in the synaptic cleft of central and peripheral synapses [5,7,8,12,41]. The approaches taken include an experimental assessment [7, sions) was chosen randomly from a Gaussian distribution with mean of 0 and a standard deviation σ given by [16,17,39]:…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Monte Carlo simulation of vesicular release, spatiotemporal distribution of glutamate in synaptic cleft and generation of postsynaptic currents

Glavinović¹

1999

Pfl�gers Archiv European Journal of Physiology

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The release of vesicular glutamate, spatiotemporal changes in glutamate concentration in the synaptic cleft and the subsequent generation of fast excitatory postsynaptic currents at a hippocampal synapse were modeled using the Monte Carlo method. It is assumed that glutamate is released from a spherical vesicle through a cylindrical fusion pore into the synaptic cleft and that S-alpha-amino-3-hydroxy -5-methyl-4-isoxazolepropionic acid (AMPA) receptors are uniformly distributed postsynaptically. The time course of change in vesicular concentration can be described by a single exponential, but a slow tail is also observed though only following the release of most of the glutamate. The time constant of decay increases with vesicular size and a lower diffusion constant, and is independent of the initial concentration, becoming markedly shorter for wider fusion pores. The cleft concentration at the fusion pore mouth is not negligible compared to vesicular concentration, especially for wider fusion pores. Lateral equilibration of glutamate is rapid, and within approximately 50 micros all AMPA receptors on average see the same concentration of glutamate. Nevertheless the single-channel current and the number of channels estimated from mean-variance plots are unreliable and different when estimated from rise- and decay-current segments. Greater saturation of AMPA receptor channels provides higher but not more accurate estimates. Two factors contribute to the variability of postsynaptic currents and render the mean-variance nonstationary analysis unreliable, even when all receptors see on average the same glutamate concentration. Firstly, the variability of the instantaneous cleft concentration of glutamate, unlike the mean concentration, first rapidly decreases before slowly increasing; the variability is greater for fewer molecules in the cleft and is spatially nonuniform. Secondly, the efficacy with which glutamate produces a response changes with time. Understanding the factors that determine the time course of vesicular content release as well as the spatiotemporal changes of glutamate concentration in the cleft is crucial for understanding the mechanism that generates postsynaptic currents.

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Parametric spectral analysis of nonstationary fluctuations of excitatory synaptic currents

et al. 2007

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We assessed on Monte-Carlo simulated excitatory post-synaptic currents the ability of autoregressive (AR)-model fitting to evaluate their fluctuations. AR-model fitting consists of a linear filter describing the process that generates the fluctuations when driven with a white noise. Its fluctuations provide a filtered version of the signal and have a spectral density depending on the properties of the linear filter. When the spectra of the non-stationary fluctuations of excitatory post-synaptic currents were estimated by fitting AR-models to the segments of current fluctuations, assumed to be stationary and independent, the parameter and spectral estimates were scattered. The scatter was much reduced if the time-variant AR-models were fitted using stochastic adaptive estimators (Kalman, recursive least squares and least mean squares). The ability of time-variant AR-models to accurately fit the current fluctuations was monitored by comparing the fluctuations with predicted fluctuations, and by evaluating the model-learning rate. The median frequency of current fluctuations, which could be rapidly tracked and estimated from the individual quantal events (either Monte-Carlo simulated or recorded from pyramidal neurons of rat hippocampus), rose during the rise phase, before declining to a lower steady-state level during the decay phase of quantal event, whereas the variance showed a broad peak. The closing rate of AMPA channels directly affects the steady-state median frequency, whereas the transient peak can be modulated by a variety of factors-number of molecules released, ability of glutamate molecules to re-enter the synaptic cleft, diffusion constant of glutamate in the cleft and opening rate of AMPA channels. In each case, the effect on the amplitude and decay time of mEPSCs and on the current fluctuations differs. Each factor thus leaves its own kinetic fingerprint arguing that the contribution of such factors can be inferred from the combined kinetic properties of individual mEPSCs.

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Monte Carlo simulation of spontaneous miniature excitatory postsynaptic currents in rat hippocampal synapse in the presence and absence of desensitization

Cited by 25 publications

References 26 publications

Block of AMPA Receptor Desensitization by a Point Mutation outside the Ligand-Binding Domain

Block of AMPA Receptor Desensitization by a Point Mutation outside the Ligand-Binding Domain

Monte Carlo simulation of vesicular release, spatiotemporal distribution of glutamate in synaptic cleft and generation of postsynaptic currents

Parametric spectral analysis of nonstationary fluctuations of excitatory synaptic currents

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