RESUMO
In obstacle-filled media, such as extracellular or intracellular lumen of brain tissue, effective ion-diffusion permeability is a key determinant of electrogenic reactions. Although this diffusion permeability is thought to depend entirely on structural features of the medium, such as porosity and tortuosity, brain tissue shows prominent nonohmic properties, the origins of which remain poorly understood. Here, we explore Monte Carlo simulations of ion diffusion in a space filled with overlapping spheres to predict that diffusion permeability of such media decreases with stronger external electric fields. This dependence increases with lower medium porosity while decreasing with radial (two-dimensional or three-dimensional) compared with homogenous (one-dimensional) fields. We test our predictions empirically in an electrolyte chamber filled with microscopic glass spheres and find good correspondence with our predictions. A theoretical insight relates this phenomenon to a disproportionately increased dwell time of diffusing ions at potential barriers (or traps) representing geometric obstacles when the field strength increases. The dependence of medium ion-diffusion permeability on electric field could be important for understanding conductivity properties of porous materials, in particular for the accurate interpretation of electric activity recordings in brain tissue.
Assuntos
Porosidade , Difusão , Condutividade Elétrica , Método de Monte Carlo , PermeabilidadeRESUMO
Decades after the discovery that ionic zinc is present at high levels in glutamatergic synaptic vesicles, where, when, and how much zinc is released during synaptic activity remains highly controversial. Here we provide a quantitative assessment of zinc dynamics in the synaptic cleft and clarify its role in the regulation of excitatory neurotransmission by combining synaptic recordings from mice deficient for zinc signaling with Monte Carlo simulations. Ambient extracellular zinc levels are too low for tonic occupation of the GluN2A-specific nanomolar zinc sites on NMDA receptors (NMDARs). However, following short trains of physiologically relevant synaptic stimuli, zinc transiently rises in the cleft and selectively inhibits postsynaptic GluN2A-NMDARs, causing changes in synaptic integration and plasticity. Our work establishes the rules of zinc action and reveals that zinc modulation extends beyond hippocampal mossy fibers to excitatory SC-CA1 synapses. By specifically moderating GluN2A-NMDAR signaling, zinc acts as a widespread activity-dependent regulator of neuronal circuits.
Assuntos
Neurônios/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Zinco/metabolismo , Animais , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Camundongos , Camundongos Transgênicos , Método de Monte CarloRESUMO
The prevailing view at present is that postsynaptic expression of the classical NMDA receptor-dependent long-term potentiation relies on an increase in the numbers of local AMPA receptors (AMPARs). This is thought to parallel an expansion of postsynaptic cell specializations, for instance dendritic spine heads, which accommodate synaptic receptor proteins. However, glutamate released into the synaptic cleft can normally activate only a hotspot of low-affinity AMPARs that occur in the vicinity of the release site. How the enlargement of the AMPAR pool is causally related to the potentiated AMPAR current remains therefore poorly understood. To understand possible scenarios of postsynaptic potentiation, here we explore a detailed Monte Carlo model of the typical small excitatory synapse. Simulations suggest that approximately 50% increase in the synaptic AMPAR current could be provided by expanding the existing AMPAR pool at the expense of 100-200% new AMPARs added at the same packing density. Alternatively, reducing the inter-receptor distances by only 30-35% could achieve a similar level of current potentiation without any changes in the receptor numbers. The NMDA receptor current also appears sensitive to the NMDA receptor crowding. Our observations provide a quantitative framework for understanding the 'resource-efficient' ways to enact use-dependent changes in the architecture of central synapses.
Assuntos
Potenciação de Longa Duração/fisiologia , Modelos Neurológicos , Receptores de AMPA/metabolismo , Transmissão Sináptica/fisiologia , Simulação por Computador , Ácido Glutâmico/metabolismo , Humanos , Método de Monte CarloRESUMO
Electric fields of synaptic currents can influence diffusion of charged neurotransmitters, such as glutamate, in the synaptic cleft. However, this phenomenon has hitherto been detected only through sustained depolarization of large principal neurons, and its adaptive significance remains unknown. Here, we find that in cerebellar synapses formed on electrically compact granule cells, a single postsynaptic action potential can retard escape of glutamate released into the cleft. This retardation boosts activation of perisynaptic group I metabotropic glutamate receptors (mGluRs), which in turn rapidly facilitates local NMDA receptor currents. The underlying mechanism relies on a Homer-containing protein scaffold, but not GPCR- or Ca(2+)-dependent signaling. Through the mGluR-NMDAR interaction, the coincidence between a postsynaptic spike and glutamate release triggers a lasting enhancement of synaptic transmission that alters the basic integrate-and-spike rule in the circuitry. Our results thus reveal an electrodiffusion-driven synaptic memory mechanism that requires high-precision coincidence detection suitable for high-fidelity circuitries.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Neurônios/fisiologia , Receptores de Glutamato Metabotrópico/metabolismo , Sinapses/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Ácido Aspártico/farmacologia , Biofísica , Proteínas de Transporte/genética , Cerebelo/citologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Arcabouço Homer , Humanos , Técnicas In Vitro , Proteínas Luminescentes/genética , Microscopia Eletrônica de Transmissão , Modelos Neurológicos , Método de Monte Carlo , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Técnicas de Patch-Clamp , Quinoxalinas/farmacologia , RNA Interferente Pequeno/genética , Ratos , Receptores de Glutamato Metabotrópico/genética , Estatísticas não Paramétricas , Sinapses/genética , Sinapses/metabolismo , Sinapsinas/genética , Sinapsinas/metabolismo , Transfecção/métodos , Proteína Vermelha FluorescenteRESUMO
Why synapses release a certain amount of neurotransmitter is poorly understood. We combined patch-clamp electrophysiology with computer simulations to estimate how much glutamate is discharged at two distinct central synapses of the rat. We found that, regardless of some uncertainty over synaptic microenvironment, synapses generate the maximal current per released glutamate molecule while maximizing signal information content. Our result suggests that synapses operate on a principle of resource optimization.
Assuntos
Cerebelo/citologia , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Modelos Neurológicos , Neurônios/fisiologia , Sinapses/metabolismo , Animais , Biofísica , Simulação por Computador , Dipeptídeos/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Entropia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Ácido Glutâmico/farmacologia , Técnicas In Vitro , Masculino , Método de Monte Carlo , Fibras Musgosas Hipocampais/fisiologia , Fibras Nervosas/fisiologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Sinapses/efeitos dos fármacosRESUMO
The synaptic response waveform, which determines signal integration properties in the brain, depends on the spatiotemporal profile of neurotransmitter in the synaptic cleft. Here, we show that electrophoretic interactions between AMPA receptor-mediated excitatory currents and negatively charged glutamate molecules accelerate the clearance of glutamate from the synaptic cleft, speeding up synaptic responses. This phenomenon is reversed upon depolarization and diminished when intracleft electric fields are weakened through a decrease in the AMPA receptor density. In contrast, the kinetics of receptor-mediated currents evoked by direct application of glutamate are voltage-independent, as are synaptic currents mediated by the electrically neutral neurotransmitter GABA. Voltage-dependent temporal tuning of excitatory synaptic responses may thus contribute to signal integration in neural circuits.
Assuntos
Potenciais Pós-Sinápticos Excitadores , Ácido Glutâmico/metabolismo , Células Piramidais/fisiologia , Receptores de AMPA/metabolismo , Sinapses/fisiologia , Animais , Células Cultivadas , Dendritos/fisiologia , Difusão , Dipeptídeos/farmacologia , Magnésio/farmacologia , Masculino , Método de Monte Carlo , Técnicas de Patch-Clamp , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/antagonistas & inibidores , Receptores de GABA/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
Signal integration in the brain is determined by the size and kinetics of rapid synaptic responses. The latter, in turn, depends on the concentration profile of neurotransmitter in the synaptic cleft. According to a traditional view, narrower clefts should correspond to higher intracleft concentrations of neurotransmitter, and therefore to the enhanced activation of synaptic receptors. Here, we argue that narrowing the cleft also increases electrical resistance of the intracleft medium and therefore reduces local receptor currents. We employ detailed theoretical analyses and Monte Carlo simulations to propose that these two contrasting phenomena result in a relatively narrow range of cleft heights at which the synaptic receptor current reaches its maximum. Over a physiological range of synaptic parameters, the "optimum" height falls between approximately 12 and 20 nm. This range is consistent with the structure of central synapses reported by electron microscopy. Therefore, our results suggest that a simple fundamental principle may underlie the synaptic cleft architecture: to maximize synaptic strength.
Assuntos
Modelos Neurológicos , Neurônios/citologia , Sinapses , Animais , Difusão , Ácido Glutâmico/química , Ácido Glutâmico/metabolismo , Humanos , Método de Monte Carlo , Neurônios/química , Neurônios/fisiologia , Receptores de AMPA/química , Receptores de AMPA/fisiologia , Sinapses/química , Sinapses/fisiologiaRESUMO
The time course of neurotransmitter in the synaptic cleft contributes substantially to the fast kinetics of synaptic signalling. Hippocampal mossy fibres (MFs), a well-characterised excitatory pathway from dentate granule cells to the hippocampus proper, form large glutamatergic synapses at branched spiny structures in CA3 pyramidal cell dendrites. To what extent transmission at these synapses is affected by retarded glutamate clearance from the large tortuous synaptic cleft is not known. Here, we propose a simple geometrical approximation representing the 'typical' geometry of thorny excrescences that form the tortuous cleft interface at a MF synapse. We then employ Monte Carlo simulations to monitor movements of 3000 individual glutamate molecules released within the cleft. The results predict that, in the absence of neuronal glutamate transporters, it should take approximately 10 ms for 50% and 60-70 ms for 90% of glutamate molecules to escape the MF synapse.