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1.
Blood Adv ; 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35446936

RESUMO

We compared the efficacy and safety of eltrombopag (ELTR) combined with immunosuppressive therapy (IST) and IST alone in treatment-naïve children with severe (SAA) and very severe (vSAA) aplastic anemia. Ninety-eight pediatric patients were randomized to receive horse antithymocyte globulin and cyclosporin A with (n=49) or without (n=49) ELTR. The primary endpoint was the overall response rate (ORR) at 4 months. After 4 months, nonresponders were crossed over to the alternative group. In all patients, the ORR in ELTR+IST and IST groups was similar (65% vs. 53%, p=0.218); however, the complete response (CR) rate was significantly higher in ELTR+IST group (31% vs. 12%, p=0.027). In severity subgroups, the ORR was 89% vs. 57% (p=0.028) in favor of IST+ELTR in SAA, but it did not differ in patients with vSAA (52% vs. 50%, p=0.902). At 6 months after the crossover, 61% of initial ELTR(-) patients achieved a response compared to 17% of initial ELTR(+) patients (p=0.016). No significant difference in ELTR+IST and IST groups was observed in the 3-year OS (89% vs. 91%, p=0.673) or the 3-year EFS (53% vs. 41%, p=0.326). There was no unexpected toxicity related to ELTR. Adding ELTR to standard IST was well tolerated and increased the CR rate. The greatest benefit from ELTR combined with IST was observed in patients with SAA, but not in those with vSAA. The second course of IST resulted in a high ORR in initial ELTR(-) patients who added ELTR and had limited efficacy among patients who received ELTR upfront. Clinicaltrials.gov #NCT03413306.

2.
ACS Nano ; 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34255478

RESUMO

Because of their unique atomic structure, 2D materials are able to create an up-to-date paradigm in fundamental science and technology on the way to engineering the band structure and electronic properties of materials on the nanoscale. One of the simplest methods along this path is the superposition of several 2D nanomaterials while simultaneously specifying the twist angle between adjacent layers (θ), which leads to the emergence of Moiré superlattices. The key challenge in 2D nanoelectronics is to obtain a nanomaterial with numerous Moiré superlattices in addition to a high carrier mobility in a stable and easy-to-fabricate material. Here, we demonstrate the possibility of synthesizing twisted multilayer graphene (tMLG) with a number of monolayers NL = 40-250 and predefined narrow ranges of θ = 3-8°, θ = 11-15°, and θ = 26-30°. A 2D nature of the electron transport is observed in the tMLG, and its carrier mobilities are close to those of twisted bilayer graphene (tBLG) (with θ = 30°) between h-BN layers. We demonstrate an undoubtful presence of numerous Moiré superlattices simultaneously throughout the entire tMLG thickness, while the periods of these superlattices are rather close to each other. This offers a challenge of producing a next generation of devices for nanoelectronics, twistronics, and neuromorphic computing for large data applications.

3.
Biophys J ; 120(10): 1942-1956, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33771472

RESUMO

We examine closed-form approximations for the equilibrium Ca2+ and buffer concentrations near a point Ca2+ source representing a Ca2+ channel, in the presence of a mobile buffer with two Ca2+ binding sites activated sequentially and possessing distinct binding affinities and kinetics. This allows us to model the impact on Ca2+ nanodomains of realistic endogenous Ca2+ buffers characterized by cooperative Ca2+ binding, such as calretinin. The approximations we present involve a combination or rational and exponential functions, whose parameters are constrained using the series interpolation method that we recently introduced for the case of simpler Ca2+ buffers with a single Ca2+ binding site. We conduct extensive parameter sensitivity analysis and show that the obtained closed-form approximations achieve reasonable qualitative accuracy for a wide range of buffer's Ca2+ binding properties and other relevant model parameters. In particular, the accuracy of the derived approximants exceeds that of the rapid buffering approximation in large portions of the relevant parameter space.


Assuntos
Cálcio , Sítios de Ligação , Tampões (Química) , Cinética
4.
Biophys J ; 119(6): 1239-1254, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32877663

RESUMO

We consider the stationary solution for the Ca2+ concentration near a point Ca2+ source describing a single-channel Ca2+ nanodomain in the presence of a single mobile Ca2+ buffer with 1:1 Ca2+ binding. We present computationally efficient approximants that estimate stationary single-channel Ca2+ nanodomains with great accuracy in broad regions of parameter space. The presented approximants have a functional form that combines rational and exponential functions, which is similar to that of the well-known excess buffer approximation and the linear approximation but with parameters estimated using two novel, to our knowledge, methods. One of the methods involves interpolation between the short-range Taylor series of the free buffer concentration and its long-range asymptotic series in inverse powers of distance from the channel. Although this method has already been used to find Padé (rational-function) approximants to single-channel Ca2+ and buffer concentrations, extending this method to interpolants combining exponential and rational functions improves accuracy in a significant fraction of the relevant parameter space. A second method is based on the variational approach and involves a global minimization of an appropriate functional with respect to parameters of the chosen approximations. An extensive parameter-sensitivity analysis is presented, comparing these two methods with previously developed approximants. Apart from increased accuracy, the strength of these approximants is that they can be extended to more realistic buffers with multiple binding sites characterized by cooperative Ca2+ binding, such as calmodulin and calretinin.


Assuntos
Cálcio , Calmodulina , Sítios de Ligação , Cálcio/metabolismo , Calmodulina/metabolismo
5.
Biophys J ; 114(5): 1204-1215, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29539405

RESUMO

Fundamental cell processes such as synaptic neurotransmitter release, endocrine hormone secretion, and myocyte contraction are controlled by highly localized calcium (Ca2+) signals resulting from brief openings of trans-membrane Ca2+ channels. On short temporal and spatial scales, the corresponding local Ca2+ nanodomains formed in the vicinity of a single or several open Ca2+ channels can be effectively approximated by quasi-stationary solutions. The rapid buffering approximation (RBA) is one of the most powerful of such approximations, and is based on the assumption of instantaneous equilibration of the bimolecular Ca2+ buffering reaction, combined with the conservation condition for the total Ca2+ and buffer molecule numbers. Previously, RBA has been generalized to an arbitrary arrangement of Ca2+ channels on a flat membrane, in the presence of any number of simple Ca2+ buffers with one-to-one Ca2+ binding stoichiometry. However, many biological buffers have multiple binding sites. For example, buffers and sensors phylogenetically related to calmodulin consist of two Ca2+-binding domains (lobes), with each domain binding two Ca2+ ions in a cooperative manner. Here we consider an extension of RBA to such buffers with two interdependent Ca2+ binding sites. We show that in the presence of such buffers, RBA solution is given by the solution to a cubic equation, analogous to the quadratic equation describing RBA in the case of a simple, one-to-one Ca2+ buffer. We examine in detail the dependence of RBA accuracy on buffering parameters, to reveal conditions under which RBA provides sufficient precision.


Assuntos
Cálcio/metabolismo , Sítios de Ligação , Espaço Intracelular/metabolismo , Cinética , Modelos Biológicos , Células Musculares/citologia , Células Musculares/metabolismo
6.
J Clin Invest ; 127(6): 2353-2364, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28481223

RESUMO

Loss of first-phase insulin secretion is an early sign of developing type 2 diabetes (T2D). Ca2+ entry through voltage-gated L-type Ca2+ channels triggers exocytosis of insulin-containing granules in pancreatic ß cells and is required for the postprandial spike in insulin secretion. Using high-resolution microscopy, we have identified a subset of docked insulin granules in human ß cells and rat-derived clonal insulin 1 (INS1) cells for which localized Ca2+ influx triggers exocytosis with high probability and minimal latency. This immediately releasable pool (IRP) of granules, identified both structurally and functionally, was absent in ß cells from human T2D donors and in INS1 cells cultured in fatty acids that mimic the diabetic state. Upon arrival at the plasma membrane, IRP granules slowly associated with 15 to 20 L-type channels. We determined that recruitment depended on a direct interaction with the synaptic protein Munc13, because expression of the II-III loop of the channel, the C2 domain of Munc13-1, or of Munc13-1 with a mutated C2 domain all disrupted L-type channel clustering at granules and ablated fast exocytosis. Thus, rapid insulin secretion requires Munc13-mediated recruitment of L-type Ca2+ channels in close proximity to insulin granules. Loss of this organization underlies disturbed insulin secretion kinetics in T2D.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Grânulos Citoplasmáticos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Sinalização do Cálcio , Células Cultivadas , Diabetes Mellitus Tipo 2/patologia , Humanos , Secreção de Insulina , Proteínas do Tecido Nervoso/metabolismo , Transporte Proteico
7.
Proc Natl Acad Sci U S A ; 112(23): E3075-84, 2015 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-26015575

RESUMO

Fast synchronous neurotransmitter release at the presynaptic active zone is triggered by local Ca(2+) signals, which are confined in their spatiotemporal extent by endogenous Ca(2+) buffers. However, it remains elusive how rapid and reliable Ca(2+) signaling can be sustained during repetitive release. Here, we established quantitative two-photon Ca(2+) imaging in cerebellar mossy fiber boutons, which fire at exceptionally high rates. We show that endogenous fixed buffers have a surprisingly low Ca(2+)-binding ratio (∼ 15) and low affinity, whereas mobile buffers have high affinity. Experimentally constrained modeling revealed that the low endogenous buffering promotes fast clearance of Ca(2+) from the active zone during repetitive firing. Measuring Ca(2+) signals at different distances from active zones with ultra-high-resolution confirmed our model predictions. Our results lead to the concept that reduced Ca(2+) buffering enables fast active zone Ca(2+) signaling, suggesting that the strength of endogenous Ca(2+) buffering limits the rate of synchronous synaptic transmission.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Animais , Feminino , Técnicas In Vitro , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurotransmissores/metabolismo
8.
J Comput Neurosci ; 33(3): 573-85, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22710936

RESUMO

Although synaptic output is known to be modulated by changes in presynaptic calcium channels, additional pathways for calcium entry into the presynaptic terminal, such as non-selective channels, could contribute to modulation of short term synaptic dynamics. We address this issue using computational modeling. The neuropeptide proctolin modulates the inhibitory synapse from the lateral pyloric (LP) to the pyloric dilator (PD) neuron, two slow-wave bursting neurons in the pyloric network of the crab Cancer borealis. Proctolin enhances the strength of this synapse and also changes its dynamics. Whereas in control saline the synapse shows depression independent of the amplitude of the presynaptic LP signal, in proctolin, with high-amplitude presynaptic LP stimulation the synapse remains depressing while low-amplitude stimulation causes facilitation. We use simple calcium-dependent release models to explore two alternative mechanisms underlying these modulatory effects. In the first model, proctolin directly targets calcium channels by changing their activation kinetics which results in gradual accumulation of calcium with low-amplitude presynaptic stimulation, leading to facilitation. The second model uses the fact that proctolin is known to activate a non-specific cation current I ( MI ). In this model, we assume that the MI channels have some permeability to calcium, modeled to be a result of slow conformation change after binding calcium. This generates a gradual increase in calcium influx into the presynaptic terminals through the modulatory channel similar to that described in the first model. Each of these models can explain the modulation of the synapse by proctolin but with different consequences for network activity.


Assuntos
Sinalização do Cálcio/fisiologia , Cálcio/fisiologia , Sinapses/fisiologia , Algoritmos , Animais , Braquiúros , Cálcio/metabolismo , Canais Iônicos/fisiologia , Modelos Neurológicos , Neuropeptídeos/fisiologia , Neurotransmissores/fisiologia , Dinâmica não Linear , Oligopeptídeos/fisiologia , Piloro/inervação , Sinapses/metabolismo
9.
Brain Res ; 1398: 126-38, 2011 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-21621748

RESUMO

The number of Ca(2+) channels contributing to the exocytosis of a single neurotransmitter vesicle in a presynaptic terminal has been a question of significant interest and debate, and is important for a full understanding of localized Ca(2+) signaling in general, and synaptic physiology in particular. This is usually estimated by measuring the sensitivity of the neurotransmitter release rate to changes in the synaptic Ca(2+) current, which is varied using appropriate voltage-clamp protocols or via pharmacological Ca(2+) channel block under the condition of constant single-channel Ca(2+) current. The slope of the resulting log-log plot of transmitter release rate versus presynaptic Ca(2+) current is termed Ca(2+)current cooperativity of exocytosis, and provides indirect information about the underlying presynaptic morphology. In this review, we discuss the relationship between the Ca(2+) current cooperativity and the average number of Ca(2+) channels participating in the exocytosis of a single vesicle, termed the Ca(2+)channel cooperativity. We relate these quantities to the morphology of the presynaptic active zone. We also review experimental studies of Ca(2+) current cooperativity and its modulation during development in different classes of synapses.


Assuntos
Canais de Cálcio/fisiologia , Sinalização do Cálcio/fisiologia , Sistema Nervoso Central/citologia , Sistema Nervoso Central/fisiologia , Exocitose/fisiologia , Sinapses/fisiologia , Animais , Canais de Cálcio/química , Humanos , Estrutura Terciária de Proteína/fisiologia
10.
J Comput Neurosci ; 31(1): 31-42, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21132359

RESUMO

Phase response is a powerful concept in the analysis of both weakly and non-weakly perturbed oscillators such as regularly spiking neurons, and is applicable if the oscillator returns to its limit cycle trajectory between successive perturbations. When the latter condition is violated, a formal application of the phase return map may yield phase values outside of its definition domain; in particular, strong synaptic inhibition may result in negative values of phase. The effect of a second perturbation arriving close to the first one is undetermined in this case. However, here we show that for a Morris-Lecar model of a spiking cell with strong time scale separation, extending the phase response function definition domain to an additional negative value branch allows to retain the accuracy of the phase response approach in the face of such strong inhibitory coupling. We use the resulting extended phase response function to accurately describe the response of a Morris-Lecar oscillator to consecutive non-weak synaptic inputs. This method is particularly useful when analyzing the dynamics of three or more non-weakly coupled cells, whereby more than one synaptic perturbation arrives per oscillation cycle into each cell. The method of perturbation prediction based on the negative-phase extension of the phase response function may be applicable to other excitable cell models characterized by slow voltage dynamics at hyperpolarized potentials.


Assuntos
Potenciais de Ação/fisiologia , Potenciais da Membrana/fisiologia , Inibição Neural/fisiologia , Neurônios/fisiologia , Transmissão Sináptica/fisiologia , Simulação por Computador , Modelos Neurológicos
11.
Nat Neurosci ; 13(11): 1348-50, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20953196

RESUMO

Presynaptic terminals favor intermediate-conductance Ca(V)2.2 (N type) over high-conductance Ca(V)1 (L type) channels for single-channel, Ca(2+) nanodomain-triggered synaptic vesicle fusion. However, the standard Ca(V)1>Ca(V)2>Ca(V)3 conductance hierarchy is based on recordings using nonphysiological divalent ion concentrations. We found that, with physiological Ca(2+) gradients, the hierarchy was Ca(V)2.2>Ca(V)1>Ca(V)3. Mathematical modeling predicts that the Ca(V)2.2 Ca(2+) nanodomain, which is ∼25% more extensive than that generated by Ca(V)1, can activate a calcium-fusion sensor located on the proximal face of the synaptic vesicle.


Assuntos
Canais de Cálcio Tipo N/fisiologia , Ativação do Canal Iônico/fisiologia , Potenciais da Membrana/fisiologia , Neurônios/fisiologia , Neurotransmissores/metabolismo , Animais , Cálcio/metabolismo , Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/classificação , Células Cultivadas , Embrião de Galinha , Relação Dose-Resposta a Droga , Gânglios Espinais/citologia , Ativação do Canal Iônico/efeitos dos fármacos , Matemática , Potenciais da Membrana/efeitos dos fármacos , Modelos Biológicos , Condução Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp/métodos , Valor Preditivo dos Testes , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Estrutura Terciária de Proteína/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Vesículas Sinápticas/metabolismo
12.
J Neurosci ; 29(39): 12196-209, 2009 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-19793978

RESUMO

Recently there has been significant interest and progress in the study of spatiotemporal dynamics of Ca(2+) that triggers exocytosis at a fast chemical synapse, which requires understanding the contribution of individual calcium channels to the release of a single vesicle. Experimental protocols provide insight into this question by probing the sensitivity of exocytosis to Ca(2+) influx. While varying extracellular or intracellular Ca(2+) concentration assesses the intrinsic biochemical Ca(2+) cooperativity of neurotransmitter release, varying the number of open Ca(2+) channels using pharmacological channel block or the tail current titration probes the cooperativity between individual Ca(2+) channels in triggering exocytosis. Despite the wide use of these Ca(2+) sensitivity measurements, their interpretation often relies on heuristic arguments. Here we provide a detailed analysis of the Ca(2+) sensitivity measures probed by these experimental protocols, present simple expressions for special cases, and demonstrate the distinction between the Ca(2+) current cooperativity, defined by the relationship between exocytosis rate and the whole-terminal Ca(2+) current magnitude, and the underlying Ca(2+) channel cooperativity, defined as the average number of channels involved in the release of a single vesicle. We find simple algebraic expressions that show that the two are different but linearly related. Further, we use three-dimensional computational modeling of buffered Ca(2+) diffusion to analyze these distinct Ca(2+) cooperativity measures, and demonstrate the role of endogenous Ca(2+) buffers on such measures. We show that buffers can either increase or decrease the Ca(2+) current cooperativity of exocytosis, depending on their concentration and the single-channel Ca(2+) current.


Assuntos
Potenciais de Ação/fisiologia , Canais de Cálcio/fisiologia , Cálcio/fisiologia , Exocitose/fisiologia , Modelos Neurológicos , Sinalização do Cálcio/fisiologia
13.
J Comput Neurosci ; 26(2): 303-20, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18690530

RESUMO

Synchronization of excitable cells coupled by reciprocal inhibition is a topic of significant interest due to the important role that inhibitory synaptic interaction plays in the generation and regulation of coherent rhythmic activity in a variety of neural systems. While recent work revealed the synchronizing influence of inhibitory coupling on the dynamics of many networks, it is known that strong coupling can destabilize phase-locked firing. Here we examine the loss of synchrony caused by an increase in inhibitory coupling in networks of type-I Morris-Lecar model oscillators, which is characterized by a period-doubling cascade and leads to mode-locked states with alternation in the firing order of the two cells, as reported recently by Maran and Canavier (J Comput Nerosci, 2008) for a network of Wang-Buzsáki model neurons. Although alternating-order firing has been previously reported as a near-synchronous state, we show that the stable phase difference between the spikes of the two Morris-Lecar cells can constitute as much as 70% of the unperturbed oscillation period. Further, we examine the generality of this phenomenon for a class of type-I oscillators that are close to their excitation thresholds, and provide an intuitive geometric description of such "leap-frog" dynamics. In the Morris-Lecar model network, the alternation in the firing order arises under the condition of fast closing of K( + ) channels at hyperpolarized potentials, which leads to slow dynamics of membrane potential upon synaptic inhibition, allowing the presynaptic cell to advance past the postsynaptic cell in each cycle of the oscillation. Further, we show that non-zero synaptic decay time is crucial for the existence of leap-frog firing in networks of phase oscillators. However, we demonstrate that leap-frog spiking can also be obtained in pulse-coupled inhibitory networks of one-dimensional oscillators with a multi-branched phase domain, for instance in a network of quadratic integrate-and-fire model cells. Finally, for the case of a homogeneous network, we establish quantitative conditions on the phase resetting properties of each cell necessary for stable alternating-order spiking, complementing the analysis of Goel and Ermentrout (Physica D 163:191-216, 2002) of the order-preserving phase transition map.


Assuntos
Modelos Neurológicos , Neurônios/fisiologia , Potenciais de Ação , Algoritmos , Simulação por Computador , Inibição Neural , Canais de Potássio/metabolismo , Transmissão Sináptica , Tempo
14.
Nanotechnology ; 19(47): 475502, 2008 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-21836273

RESUMO

Extraordinary Hall effect probes with 160 nm × 160 nm working area were fabricated using photo- and electron-beam lithographic procedures with the aim of direct measurements of MFM cantilever tip magnetic properties. The magnetic field sensitivity of the probes was 35 Ω T(-1). Magnetic induction of the MFM cantilever tips coated by Co and SmCo films was measured with the probes. It was shown that the resolution of the probes was of the order of 10 nm.

15.
J Gen Physiol ; 129(6): 477-83, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17535960

RESUMO

Lanthanide gadolinium (Gd(3+)) blocks Ca(V)1.2 channels at the selectivity filter. Here we investigated whether Gd(3+) block interferes with Ca(2+)-dependent inactivation, which requires Ca(2+) entry through the same site. Using brief pulses to 200 mV that relieve Gd(3+) block but not inactivation, we monitored how the proportions of open and open-blocked channels change during inactivation. We found that blocked channels inactivate much less. This is expected for Gd(3+) block of the Ca(2+) influx that enhances inactivation. However, we also found that the extent of Gd(3+) block did not change when inactivation was reduced by abolition of Ca(2+)/calmodulin interaction, showing that Gd(3+) does not block the inactivated channel. Thus, Gd(3+) block and inactivation are mutually exclusive, suggesting action at a common site. These observations suggest that inactivation causes a change at the selectivity filter that either hides the Gd(3+) site or reduces its affinity, or that Ca(2+) occupies the binding site at the selectivity filter in inactivated channels. The latter possibility is supported by previous findings that the EEQE mutation of the selectivity EEEE locus is void of Ca(2+)-dependent inactivation (Zong Z.Q., J.Y. Zhou, and T. Tanabe. 1994. Biochem. Biophys. Res. Commun. 201:1117-11123), and that Ca(2+)-inactivated channels conduct Na(+) when Ca(2+) is removed from the extracellular medium (Babich O., D. Isaev, and R. Shirokov. 2005. J. Physiol. 565:709-717). Based on these results, we propose that inactivation increases affinity of the selectivity filter for Ca(2+) so that Ca(2+) ion blocks the pore. A minimal model, in which the inactivation "gate" is an increase in affinity of the selectivity filter for permeating ions, successfully simulates the characteristic U-shaped voltage dependence of inactivation in Ca(2+).


Assuntos
Bloqueadores dos Canais de Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Cálcio/metabolismo , Gadolínio/metabolismo , Ativação do Canal Iônico , Animais , Bário/metabolismo , Ligação Competitiva , Canais de Cálcio Tipo L/química , Linhagem Celular , Permeabilidade da Membrana Celular , Humanos , Cinética , Potenciais da Membrana , Modelos Biológicos , Técnicas de Patch-Clamp , Conformação Proteica , Subunidades Proteicas/metabolismo , Estrôncio/metabolismo , Transfecção
16.
J Comput Neurosci ; 23(2): 169-87, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17440801

RESUMO

Out-of-phase bursting is a functionally important behavior displayed by central pattern generators and other neural circuits. Understanding this complex activity requires the knowledge of the interplay between the intrinsic cell properties and the properties of synaptic coupling between the cells. Here we describe a simple method that allows us to investigate the existence and stability of anti-phase bursting solutions in a network of two spiking neurons, each possessing a T-type calcium current and coupled by reciprocal inhibition. We derive a one-dimensional map which fully characterizes the genesis and regulation of anti-phase bursting arising from the interaction of the T-current properties with the properties of synaptic inhibition. This map is the burst length return map formed as the composition of two distinct one-dimensional maps that are each regulated by a different set of model parameters. Although each map is constructed using the properties of a single isolated model neuron, the composition of the two maps accurately captures the behavior of the full network. We analyze the parameter sensitivity of these maps to determine the influence of both the intrinsic cell properties and the synaptic properties on the burst length, and to find the conditions under which multistability of several bursting solutions is achieved. Although the derivation of the map relies on a number of simplifying assumptions, we discuss how the principle features of this dimensional reduction method could be extended to more realistic model networks.


Assuntos
Potenciais de Ação/fisiologia , Modelos Neurológicos , Inibição Neural/fisiologia , Neurônios/fisiologia , Dinâmica não Linear , Animais , Comunicação Celular/fisiologia , Rede Nervosa , Redes Neurais de Computação
17.
J Neurophysiol ; 96(6): 3389-97, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16971687

RESUMO

Facilitation is a transient stimulation-induced increase in synaptic response, a ubiquitous form of short-term synaptic plasticity that can regulate synaptic transmission on fast time scales. In their pioneering work, Katz and Miledi and Rahamimoff demonstrated the dependence of facilitation on presynaptic Ca(2+) influx and proposed that facilitation results from the accumulation of residual Ca(2+) bound to vesicle release triggers. However, this bound Ca(2+) hypothesis appears to contradict the evidence that facilitation is reduced by exogenous Ca(2+) buffers. This conclusion led to a widely held view that facilitation must depend solely on the accumulation of Ca(2+) in free form. Here we consider a more realistic implementation of the bound Ca(2+) mechanism, taking into account spatial diffusion of Ca(2+), and show that a model with slow Ca(2+) unbinding steps can retain sensitivity to free residual Ca(2+). We demonstrate that this model agrees with the facilitation accumulation time course and its biphasic decay exhibited by the crayfish inhibitor neuromuscular junction (NMJ) and relies on fewer assumptions than the most recent variants of the free residual Ca(2+) hypothesis. Further, we show that the bound Ca(2+) accumulation is consistent with Kamiya and Zucker's experimental results, which revealed that photolytic liberation of a fast Ca(2+) buffer decreases the synaptic response within milliseconds. We conclude that Ca(2+) binding processes with slow unbinding times (tens to hundreds of milliseconds) constitute a viable mechanism of synaptic facilitation at some synapses and discuss the experimental evidence for such a mechanism.


Assuntos
Astacoidea/fisiologia , Cálcio/metabolismo , Cálcio/fisiologia , Sinapses/fisiologia , Potenciais de Ação/fisiologia , Algoritmos , Animais , Tampões (Química) , Difusão , Estimulação Elétrica , Técnicas In Vitro , Modelos Neurológicos , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/fisiologia , Sinapses/efeitos dos fármacos
18.
Biophys J ; 86(5): 2691-709, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15111389

RESUMO

Synaptic facilitation (SF) is a ubiquitous form of short-term plasticity, regulating synaptic dynamics on fast timescales. Although SF is known to depend on the presynaptic accumulation of Ca(2+), its precise mechanism is still under debate. Recently it has been shown that at certain central synapses SF results at least in part from the progressive saturation of an endogenous Ca(2+) buffer (Blatow et al., 2003), as proposed by Klingauf and Neher (1997). Using computer simulations, we study the magnitude of SF that can be achieved by a buffer saturation mechanism (BSM), and explore its dependence on the endogenous buffering properties. We find that a high SF magnitude can be obtained either by a global saturation of a highly mobile buffer in the entire presynaptic terminal, or a local saturation of a completely immobilized buffer. A characteristic feature of BSM in both cases is that SF magnitude depends nonmonotonically on the buffer concentration. In agreement with results of Blatow et al. (2003), we find that SF grows with increasing distance from the Ca(2+) channel cluster, and increases with increasing external Ca(2+), [Ca(2+)](ext), for small levels of [Ca(2+)](ext). We compare our modeling results with the experimental properties of SF at the crayfish neuromuscular junction, and find that the saturation of an endogenous mobile buffer can explain the observed SF magnitude and its supralinear accumulation time course. However, we show that the BSM predicts slowing of the SF decay rate in the presence of exogenous Ca(2+) buffers, contrary to experimental observations at the crayfish neuromuscular junction. Further modeling and data are required to resolve this aspect of the BSM.


Assuntos
Tampões (Química) , Animais , Astacoidea , Sítios de Ligação , Biofísica/métodos , Cálcio/química , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Simulação por Computador , Corantes Fluorescentes/farmacologia , Fura-2/farmacologia , Cinética , Modelos Teóricos , Junção Neuromuscular , Fatores de Tempo
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