RESUMO
A recent report of autosomal-recessive primary isolated dystonia (DYT2 dystonia) identified mutations in HPCA, a gene encoding a neuronal calcium sensor protein, hippocalcin (HPCA), as the cause of this disease. However, how mutant HPCA leads to neuronal dysfunction remains unknown. Using a multidisciplinary approach, we demonstrated the failure of dystonic N75K HPCA mutant to decode short bursts of action potentials and theta rhythms in hippocampal neurons by its Ca2+-dependent translocation to the plasma membrane. This translocation suppresses neuronal activity via slow afterhyperpolarization (sAHP) and we found that the N75K mutant could not control sAHP during physiologically relevant neuronal activation. Simulations based on the obtained experimental results directly demonstrated an increased excitability in neurons expressing N75K mutant instead of wild type (WT) HPCA. In conclusion, our study identifies sAHP as a downstream cellular target perturbed by N75K mutation in DYT2 dystonia, demonstrates its impact on neuronal excitability, and suggests a potential therapeutic strategy to efficiently treat DYT2.
Assuntos
Potenciais de Ação/fisiologia , Sinalização do Cálcio/fisiologia , Distonia Muscular Deformante/genética , Distonia Muscular Deformante/fisiopatologia , Hipocalcina/genética , Mutação/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Distonia Muscular Deformante/metabolismo , Feminino , Células HEK293 , Hipocalcina/metabolismo , Hipocampo/citologia , Hipocampo/fisiologia , Humanos , Masculino , Ratos , Ratos WistarRESUMO
In computer models, we studied instantaneous (time-varying) current-voltage relationships (iIVs) of populations of ion channels characteristic of the membrane of different type excitable cells, of which the responses to electrical stimuli essentially differ: giant squid axon (Hodgkin-Huxley model), cardiomyocyte, dendrites of CA3 hippocampal pyramidal neurons and Purkinje neurons of the cerebellum. The membrane potential was stepped from the rest level to a certain depolarization test level that was clamped for a certain time, and the total current was measured at different moments after the step onset. For each iIV zero-current points (potentials) were determined. A set of such points, which were situated on the limb of iIV positive slop and corresponded to the state of high membrane depolarization (excitation state, upstate) at different time moments, were used to characterize the dynamics of the excitation state in time. With these indicators the axon membrane was characterized by a single excitation state that rapidly occurred (0.25 ms) and was short-lasting (decayed from -45 to 40 mV during life-time of 5.5 ms). There were two such states of the membrane of cardiomyocyte. The first one was early, rapidly occurring and short-living (rapidly relaxing). It occurred shortly after the depolarization start and lasted for 14.5 ms. The second one was late, slowly rising and long-lasting (occurred with a 7.5-ms delay, increased from 11 to 46 mV in 39 ms and then relaxed lasting for 623 ms in total). The dendritic membrane ofCA3 neurons had one long-lasting excitation state that occurred shortly after the depolarization shift, first rapidly relaxed during 3 ms from initial 30 mV level to -10 mV and then slowly, in 80 ms, stabilized at the level of -20 mV. In the Purkinje neuron membrane two short-lasting and one very long-lasting excitation states were revealed. The first state of very high (>100 mV) depolarization relaxed to 4 mV in 0.8 ms. Shortly before its vanishing, at 0.7 ms, the second short-lasting state emerged, which relaxed in 1 ms from -22 mV to -48 mV. At 1.8 ms a new excitation state emerged, which after a transient relaxation stabilized at -29.65 mV starting from 88 ms. Thus, iIVs allowed disclosing a fine organization of the states of electrical excitation of the membrane and revealing, in populations of ion channels of different content, existence of different number of the mentioned states, which differ from each other in occurrence time and life-time.
Assuntos
Potenciais de Ação/fisiologia , Ativação do Canal Iônico/fisiologia , Canais Iônicos/fisiologia , Animais , Axônios/fisiologia , Decapodiformes , Dendritos/fisiologia , Modelos Neurológicos , Miócitos Cardíacos/fisiologia , Especificidade de Órgãos , Técnicas de Patch-Clamp , Células de Purkinje/fisiologia , Células Piramidais/fisiologiaRESUMO
The functional geometry of the reconstructed dendritic arborization of Purkinje neurons is the object of this work. The combined effects of the local geometry of the dendritic branches and of the membrane mechanisms are computed in passive configuration to obtain the electrotonic structure of the arborization. Steady-currents applied to the soma and expressed as a function of the path distance from the soma form different clusters of profiles in which dendritic branches are similar in voltages and current transfer effectiveness. The locations of the different clusters are mapped on the dendrograms and 3D representations of the arborization. It reveals the presence of different spatial dendritic sectors clearly separated in 3D space that shape the arborization in ordered electrical domains, each with similar passive charge transfer efficiencies. Further simulations are performed in active configuration with a realistic cocktail of conductances to find out whether similar spatial domains found in the passive model also characterize the active dendritic arborization. During tonic activation of excitatory synaptic inputs homogeneously distributed over the whole arborization, the Purkinje cell generates regular oscillatory potentials. The temporal patterns of the electrical oscillations induce similar spatial sectors in the arborization as those observed in the passive electrotonic structure. By taking a video of the dendritic maps of the membrane potentials during a single oscillation, we demonstrate that the functional dendritic field of a Purkinje neuron displays dynamic changes which occur in the spatial distribution of membrane potentials in the course of the oscillation. We conclude that the branching pattern of the arborization explains such continuous reconfiguration and discuss its functional implications.
Assuntos
Córtex Cerebelar/fisiologia , Dendritos/fisiologia , Modelos Neurológicos , Células de Purkinje/fisiologia , Transmissão Sináptica/fisiologia , Animais , Relógios Biológicos/fisiologia , Compartimento Celular/fisiologia , Polaridade Celular/fisiologia , Forma Celular/fisiologia , Córtex Cerebelar/citologia , Simulação por Computador , Dendritos/ultraestrutura , Processamento de Imagem Assistida por Computador , Potenciais da Membrana/fisiologia , Técnicas de Cultura de Órgãos , Células de Purkinje/citologia , Ratos , Sinapses/fisiologiaRESUMO
The aim of this work was to explore the electrical spatial profile of the dendritic arborization during membrane potential oscillations of a bistable motoneuron. Computational simulations provided the spatial counterparts of the temporal dynamics of bistability and allowed simultaneous depiction the electrical states of any sites in the arborization. We assumed that the dendritic membrane had homogeneously distributed specific electrical properties and was equipped with a cocktail of passive extrasynaptic and NMDA synaptic conductances. The electrical conditions for evoking bistability in a single isopotential compartment and in a whole dendritic arborization were computed and showed differences, revealing a crucial effect of dendritic geometry. Snapshots of the whole arborization during bistability revealed the spatial distribution of the density of the transmembrane current generated at the synapses and the effectiveness of the current transfer from any dendritic site to the soma. These functional maps changed dynamically according to the phase of the oscillatory cycle. In the low depolarization state, the current density was low in the proximal dendrites and higher in the distal parts of the arborization while the transfer effectiveness varied in a narrow range with small differences between proximal and distal dendritic segments. When the neuron switched to high depolarization state, the current density was high in the proximal dendrites and low in the distal branches while a large domain of the dendritic field became electrically disconnected beyond 200 micro m from the soma with a null transfer efficiency. These spatial reconfigurations affected dynamically the size and shape of the functional dendritic field and were strongly geometry-dependent.
Assuntos
Nervo Abducente/fisiologia , Potenciais de Ação/fisiologia , Membrana Celular/fisiologia , Dendritos/fisiologia , Neurônios Motores/fisiologia , Ponte/fisiologia , Transmissão Sináptica/fisiologia , Nervo Abducente/citologia , Animais , Tamanho Celular/fisiologia , Dendritos/ultraestrutura , Modelos Neurológicos , Neurônios Motores/citologia , Ponte/citologia , Ratos , Receptores de N-Metil-D-Aspartato/fisiologia , Sinapses/fisiologiaRESUMO
Topographical maps of membrane voltages were obtained during action potentials by imaging, at 1 microm resolution, live dissociated neurons stained with the voltage sensitive dye RH237. We demonstrate with a theoretical approach that the spatial patterns in the images result from the distribution of net positive charges condensed in the inner sites of the membrane where clusters of open ionic channels are located. We observed that, in our biological images, this spatial distribution of open channels varies randomly from trial to trial while the action potentials recorded by the microelectrode display similar amplitudes and time-courses. The random differences in size and intensity of the spatial patterns in the images are best evidenced when the time of observation coincides with the duration of single action potentials. This spatial variability is explained by the fact that only part of the channel population generates an action potential and that different channels open in turn in different trials due to their stochastic operation. Such spatial flicker modifies the direction of lateral current along the neuronal membrane and may have important consequences on the intrinsic processing capabilities of the neuron.
Assuntos
Potenciais de Ação/fisiologia , Membrana Celular/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Canais de Sódio/metabolismo , Animais , Animais Recém-Nascidos , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Células Cultivadas , Estimulação Elétrica , Corantes Fluorescentes/farmacocinética , Processamento de Imagem Assistida por Computador , Microeletrodos , Microscopia de Vídeo , Modelos Neurológicos , Neurônios/efeitos dos fármacos , Gânglio Nodoso/citologia , Gânglio Nodoso/efeitos dos fármacos , Gânglio Nodoso/fisiologia , Compostos de Piridínio/farmacocinética , Ratos , Canais de Sódio/efeitos dos fármacosRESUMO
A neuron in vivo receives a continuous bombardment of synaptic inputs that modify the integrative properties of dendritic arborizations by changing the specific membrane resistance (R(m)). To address the mechanisms by which the synaptic background activity transforms the charge transfer effectiveness (T(x)) of a dendritic arborization, the authors simulated a neuron at rest and a highly excited neuron. After in vivo identification of the motoneurons recorded and stained intracellularly, the motoneuron arborizations were reconstructed at high spatial resolution. The neuronal model was constrained by the geometric data describing the numerized arborization. The electrotonic structure and T(x) were computed under different R(m) values to mimic a highly excited neuron (1 kOhm x cm(2)) and a neuron at rest (100 kOhm x cm(2)). The authors found that the shape and the size of the effective dendritic fields varied in the function of R(m). In the highly excited neuron, the effective dendritic field was reduced spatially by switching off most of the distal dendritic branches, which were disconnected functionally from the somata. At rest, the entire dendritic field was highly efficient in transferring current to the somata, but there was a lack of spatial discrimination. Because the large motoneurons are more sensitive to variations in the upper range of R(m), they switch off their distal dendrites before the small motoneurons. Thus, the same anatomic structure that shrinks or expands according to the background synaptic activity can select the types of its synaptic inputs. The results of this study demonstrate that these reconfigurations of the effective dendritic field of the motoneurons are activity-dependent and geometry-dependent.
Assuntos
Dendritos/fisiologia , Modelos Neurológicos , Neurônios Motores/fisiologia , Animais , Anuros , Gatos , Dendritos/ultraestrutura , Neurônios Motores/citologia , RatosRESUMO
In a model of a single synapse with a circular contact zone and a single concentric zone containing receptor-gated channels, we studied the dependence of the synaptic current on the synaptic cleft width and on the relative size of the receptor zone. During synaptic excitation, the extracellular current entered the cleft and flowed into the postsynaptic cell through receptor channels distributed homogeneously over the receptor zone. The membrane potential and channel currents were smaller toward the cleft center if compared to the cleft edges. This radial gradient was due to the voltage drop produced by the synaptic current on the cleft resistance. The total synaptic current conducted by the same number of open channels was sensitive to changes in the receptor zone radius and the cleft width. We conclude that synaptic geometry may affect synaptic currents by defining the volume resistor of the cleft. The in-series connection of the resistances of the intracleft medium and the receptor channels plays the role of the synaptic voltage divider. This voltage dividing effect should be taken into account when the conductance of single channels or synaptic contacts is estimated from experimental measurements of voltage-current relationships.
Assuntos
Modelos Neurológicos , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Condutividade Elétrica , Potenciais da Membrana , Reprodutibilidade dos TestesRESUMO
We analysed physical forces that act on synaptic receptor-channels following the release of neurotransmitter. These forces are: 1) electrostatic interaction between receptors, 2) stochastic Brownian diffusion in the membrane, 3) transient electric field force generated by currents through open channels, 4) viscous drag force elicited by the flowing molecules and 5) strong in-membrane friction. By considering alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptors, we show that, depending on the size and electrophoretic charge of the extracellular receptor domain, release of an excitatory neurotransmitter (glutamate) can induce receptor clustering towards the release site on a fast time scale (8-100 ms). This clustering progresses whenever repetitive synaptic activation exceeds a critical frequency (20-100 s(-1), depending on the currents through individual channels). As a result, a higher proportion of the receptors is exposed to higher glutamate levels. This should increase by 50-100% the peak synaptic current induced by the same amount of released neurotransmitter. In order for this mechanism to contribute to long-term changes of synaptic efficacy, we consider the possibility that the in-membrane motility of the AMPA receptors is transiently increased during synaptic activity, e. g., through the breakage of receptor anchors in the postsynaptic membrane due to activation of N-methyl-d-aspartic acid receptors.
Assuntos
Receptores de AMPA/fisiologia , Sinapses/fisiologia , Ácido Glutâmico/metabolismo , Modelos Neurológicos , Distribuição Normal , Receptores de N-Metil-D-Aspartato/fisiologia , Membranas Sinápticas/fisiologiaRESUMO
The impact of dendritic geometry on somatopetal transfer of the current generated by steady uniform activation of excitatory synaptic conductance distributed over passive, or active (Hodgkin-Huxley type), dendrites was studied in simulated neurons. Such tonic activation was delivered to the uniform dendrite and to the dendrites with symmetric or asymmetric branching with various ratios of branch diameters. Transfer effectiveness of the dendrites with distributed sources was estimated by the core current increment directly related to the total membrane current per unit path length. The effectiveness decreased with increasing path distance from the soma along uniform branches. The primary reason for this was the asymmetry of somatopetal vs somatofugal input core conductance met by synaptic current due to a greater leak conductance at the proximal end of the dendrite. Under these conditions, an increasing somatopetal core current and a corresponding drop of the depolarization membrane potential occurred. The voltage-dependent extrasynaptic conductances, if present, followed this depolarization. Consequently, the driving potential and membrane current densities decreased with increasing path distance from the soma. All path profiles were perturbed at bifurcations, being identical in symmetrical branches and diverging in asymmetrical ones. These perturbations were caused by voltage gradient breaks (abrupt change in the profile slope) occurring at the branching node due to coincident inhomogeneity of the dendritic core cross-section area and its conductance. The gradient was greater on the side of the smaller effective cross-section. Correspondingly, the path profiles of the somatopetal current transfer effectiveness were broken and/or diverged. The dendrites, their paths, and sites which were more effective in the current transfer from distributed sources were also more effective in the transfer from single-site inputs. The effectiveness of the active dendrite depended on the activation-inactivation kinetics of its voltage-gated conductances. In particular, dendrites with the same geometry were less effective with the Hodgkin-Huxley membrane than with the passive membrane, because of the effect of the noninactivating K(+)-conductance associated with the hyperpolarization equilibrium potential. Such electrogeometrical coupling may form a basis for path-dependent input-output conversion in the dendritic neurons, as the output discharge rate is defined by the net current delivered to the soma.
Assuntos
Dendritos/fisiologia , Modelos Neurológicos , Condução Nervosa/fisiologia , Animais , Cibernética , Potenciais da Membrana , Sinapses/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
Simulation studies were performed in a model of neuronal dendrite with Na+ and K+ channels and with ionotropic and metabotropic glutamate receptors. The ionotropic receptors were either N-methyl-D-aspartate (NMDA)-sensitive, voltage-dependent, and permeable to Ca2+, Na+, and K+, or non-NMDA-sensitive, voltage-independent, and permeable to Na+ and K+. The metabotropic receptors provided a catalytic effect on Ca2+-induced Ca2+ release from intracellular stores. Local intracellular concentration [Ca2+]i in the cytoplasm was changed because of exchange with the stores, axial diffusion, and transmembrane inward passive and outward pump fluxes. Tonic activation of ionotropic and metabotropic receptors in a particular range of intensities triggered the formation of spatially periodic [Ca2+]i hot and cold bands arising from an initial uniform state. The period and width of the bands were smaller at higher levels of tonic NMDA activation and higher metabotropically controlled rates of Ca2+-induced Ca2+ release. The bandwidths also depended on the dendrite diameter, the specific membrane, and cytoplasm resistivity. This activity-induced pattern led to long-term, spatially inhomogeneous change in local excitatory postsynaptic potentials (EPSPs) of NMDA synapses phasically activated with the same presynaptic intensity. The phasic EPSPs were potentiated if the synapse occurred in the hot band.
Assuntos
Cálcio/fisiologia , Dendritos/fisiologia , Modelos Neurológicos , Plasticidade Neuronal , Neurônios/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Sinapses/fisiologia , Animais , Cálcio/farmacologia , Canais de Cálcio/fisiologia , Simulação por Computador , Potenciais Evocados , Ácido Glutâmico/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , N-Metilaspartato/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Canais de Potássio/fisiologia , Canais de Sódio/fisiologia , Sinapses/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
Steady state longitudinal distributions of (a) the density of channels conducting an inward transmembrane current of cations, (b) the submembrane concentrations of these cations, and (c) the resting membrane potential, were investigated in a phenomenological model of a cylinder-shaped dendritic process of the neuron. It was found that spatially non-uniform patterns of these distributions occur only if one of the following conditions held (i) an increase in the intracellular concentration of cations conducting an inward passive transmembrane current amplified the active efflux of those cations by the pump and attenuated their passive influx through the voltage dependent channels, with amplification of the efflux lower than attenuation of the influx; (ii) molecules of mobile channels bore a negative electrophoretic charge exposed to the intracellular space and were subject to lateral electrodiffusion in the membrane; (iii) the cations induced a further release of cations from intracellular stores. Numerical simulation studies of the membrane with Na and K channels and Na/K pumps with conditions (i) and (ii) have demonstrated the possibility of the creation of inhomogeneous patterns in the neurites. These inhomogeneous patterns are dissipative structures (DSs), and they can be spatially periodic.
Assuntos
Dendritos/fisiologia , Eletrofisiologia , Modelos Neurológicos , Neurônios/fisiologia , Matemática , Canais de Potássio/fisiologia , Canais de Sódio/fisiologia , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Intracellular recording of abducens motoneurons in vivo has shown that ionophoretic applications of N-methyl-D-aspartate produced long-lasting membrane potential oscillations including a slow depolarization plateau with a burst of fast action potentials. This complex N-methyl-D-aspartate pattern was reproduced in the model of abducens motoneuron in vivo identified, intracellularly stained with horseradish peroxidase and reconstructed at high spatial resolution. The excitable soma of the simulated cell contained voltage-gated Ca, Na and K conductances, N-methyl-D-aspartate-gated voltage-sensitive Ca-Na-K conductance and Ca-dependent K conductance. The dendrite was passive either completely or with the exception of branching nodes containing N-methyl-D-aspartate conductances of the same slow kinetics but of lower values than at the soma. In the completely passive case, the N-methyl-D-aspartate pattern decayed with different rates along different dendritic paths depending on the geometry and topology of the reconstructed dendrite. The branches formed four clusters discriminated in somatofugal attenuations of steady voltages, and were correspondingly discriminated in attenuation of the complex N-methyl-D-aspartate pattern. Fast spikes decayed more than the slow depolarization plateau so that the prevalence of slow over fast components in the transformed pattern increased with somatofugal path distance. As a consequence, the lower the electrotonic effectiveness of a branch in the cluster or in the whole arborization, the lower both the voltage level and the frequency range of its voltage modulation by N-methyl-D-aspartate oscillations. In the case of active branching points, the somatic pattern changed depending on the level of activation of dendritic N-methyl-D-aspartate conductances with slow kinetics of voltage sensitivity. The higher this level, the longer the plateau and burst, and the greater the discharge rate; and the spikes in the burst were smaller. When the pattern spread in the dendrite, the fast spikes decayed and the slow plateau was boosted, with a greater effect along the somatofugal path containing more branching points. These results show how the somatofugal back-invasion along the dendrites by activity patterns generated at the soma can tune voltage-sensitive dendritic conductances. The dendritic back-invasion is geometry- and topology-dependent. It is proposed as a subtle feedback mechanism for the neuron to control its own synaptic inputs.
Assuntos
Dendritos/fisiologia , Modelos Neurológicos , Neurônios Motores/fisiologia , Músculo Esquelético/inervação , N-Metilaspartato/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Simulação por Computador , Dendritos/efeitos dos fármacos , Ativação do Canal Iônico , Canais Iônicos/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Oscilometria , Fatores de TempoRESUMO
Recent experimental findings (Yuste R. and Denk W. (1995) Nature 375, 682-684) suggest that dendritic spines possess excitable membranes. Theoretically, it was shown earlier that the shape of active spines can significantly affect somatopetal synaptic signal transfer. Studies of long-term potentiation in the hippocampus have related the increased synaptic efficacy to a number of structural modifications of spines, including an increased number of branched spines [Trommald M. et al. (1990) In Neurotoxicity of Excitatory Amino Acids, pp. 163-174. Raven Press, New York] and a strengthened capability for spines to alter their spatial positions [Hosokawa T. et al. (1995) J. Neurosci. 15, 5560-5573]. In the present simulation study, the potential physiological impact of several types of spine changes was examined in a compartmental neuron model built using the neuromodelling software NEURON [Hines M. (1993) In Neural Systems: Analysis and Modeling, pp. 127-136. Kluwer Academic, Norwell, MA]. The model included 30 complex spines, with dual component synaptic currents and mechanisms of Ca2+ uptake, diffusion, binding and extrusion within spine heads. The results show that local clustering properties of spine distributions along dendrites are unlikely to affect synaptic efficacy. However, partial fusion of active spines, which results in formation of spine branches, or subtle changes in spine branch positions, could alone significantly increase synaptic signal transfer. These data illustrate possible mechanisms whereby subtle morphological changes in dendritic spines (compatible with changes reported in the literature) may be linked to the cellular mechanisms of learning and memory.
Assuntos
Simulação por Computador , Dendritos/ultraestrutura , Modelos Neurológicos , Sinapses/fisiologia , Cálcio/metabolismo , Dendritos/fisiologia , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologiaRESUMO
1. In vivo experiments have shown that extracellular microelectrophoretic application of N-methyl-D-aspartate (NMDA) induced oscillatory plateau potentials with bursts of action potentials in rat abducens motoneurons. The period of these slow NMDA oscillations could be altered by single trigeminal non-NMDA excitatory input delivered at low frequency during the NMDA oscillations. 2. A resetting of the oscillations was observed depending on the phase of slow oscillatory cycle during which the trigeminal excitation occurred. 3. We investigated local mechanisms responsible for the phase-dependent modifications of NMDA oscillations, including contributions of voltage and concentration transients, in the mathematical model of the isopotential membrane compartment equipped with voltage-gated Na+, K+, and Ca2+ channels, with Ca2+-dependent K+ channels, and with ligand-gated NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels. The faithful model was constructed with the use of models described earlier, which were modified by increasing time constants of kinetic variables of all voltage-gated conductances and by including coupled dynamics of voltages and ion concentrations. The changes in ion concentrations were produced near the membrane by transmembrane currents and removal mechanisms (pumps, diffusion). 4. This work focuses on local arrangement of voltage- and ligand-gated conductances and on local ion concentration changes in two separate pools: the postsynaptic pool of AMPA receptors and the extrasynaptic pool. In terms of the electrotonic and diffusional length constants, these pools were electrotonically close but diffusionally remote. 5. It was found that the effect of resetting can be produced by a local interaction between plateau and spike-generating conductances and glutamate receptors. 6. In vivo phase-dependent interactions between NMDA oscillations and AMPA synaptic input were reproduced by the local model only when changes in intracellular sodium and extracellular potassium concentrations were taken into account and the mechanisms of ion removal from postsynaptic pools had slower kinetics than the fast pump system operating in the extracellular pool. 7. Postsynaptic changes in ion concentrations of Na+ and K+ in intra- and extracellular layers near the membrane shift of Nernst equilibrium potentials for these ions depending on the phase of activation of synaptic input. Thus Na+ and k+ components of all transmembrane currents involved in the pattern generation are differently affected by synaptic action during the oscillations. We conclude that slow postsynaptic changes in ion concentrations near the membrane play a key role in the resetting of the NMDA oscillations.
Assuntos
Nervo Abducente/fisiologia , Neurônios Motores/fisiologia , N-Metilaspartato/fisiologia , Sinapses/fisiologia , Nervo Abducente/citologia , Nervo Abducente/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Ativação do Canal Iônico , Canais Iônicos/fisiologia , Masculino , Modelos Neurológicos , Neurônios Motores/efeitos dos fármacos , N-Metilaspartato/farmacologia , Potássio/metabolismo , Ratos , Ratos Wistar , Receptores de AMPA/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Sódio/metabolismo , Sinapses/efeitos dos fármacos , Nervo Trigêmeo/fisiologiaRESUMO
The relationships between somatofugal electronic voltage spread, somatopetal charge transfer and non-uniform geometry of the neuronal dendrites were studied on the basis of the linear cable theory. It is demonstrated that for the dendritic arborization of arbitrary geometry, the path distribution of the relative effectiveness of somatopetal synaptic charge transfer defined as in Barrett and Crill (1974) is identical to that of the somatofugal steady electronic voltage normalized to the voltage at the soma. The features of both distributions are determined by breaks in the voltage gradient (the slope of monotonic voltage decay) at the sites of local non-uniformity of the dendritic geometry, such as abrupt change in diameter and asymmetric branching. If the membrane- and cytoplasm-specific electrical parameters are assumed as uniform and the branch diameter as piece-wise uniform, then at any site of step change the square reciprocal ratio of the pre- and poststep diameters determines the ratio of the pre- and poststep electronic gradients. At branching points this ratio is modulated by partition of the core current between the daughter branches in proportion to their input conductances depending on global geometries of the daughter subtrees originating there. Thus, simply computed steady somatofugal voltages provide a physiologically meaningful estimation of the relative influence of synaptic inputs in different parts of the dendritic arborization on the output of the neuron.
Assuntos
Dendritos/fisiologia , Sinapses/fisiologia , Tamanho Celular/fisiologia , Cibernética , Eletrofisiologia , Matemática , Modelos BiológicosRESUMO
A region of possible location of potassium-conducting synapses responsible for generation of "slow", or "long-term" IPSPs has been determined in computer experiments with the use of neuroscience-oriented software program CRONA on the basis of data of measurement of reversal potential of such IPSPs under natural experiments. Such geometrical parameters as dimensions of neuronal dendritic branches and intracellular potassium concentration have been studied for their effect on determination of the above-mentioned region using the results of natural experimental studies of interaction of long-term IPSPs with polarizing currents. It is shown that synaptic inputs under investigation have non-somatic location and the region of their location on apical dendrites is between 110 and 460 microns from the soma.
Assuntos
Simulação por Computador , Modelos Neurológicos , Neurônios/fisiologia , Sinapses/fisiologia , Dendritos/ultraestrutura , Potenciais Evocados/fisiologia , Neurônios/ultraestrutura , Software , Fatores de TempoRESUMO
A mathematical apparatus of computer modelling was elaborated reflecting more completely the real morphological and electrophysiological features of axons and dendrites without restrictions and simplifications which were typical of the existing models of these structures. Equivalent electrical circuits of branching axons and dendrites were constructed with in-series and node connections of standard four-terminal networks corresponding to elementary segments with active or passive membrane. Basing on these circuits the equations were obtained describing electrical phenomena in branching neuronal processes. They were generalized for the case of multiple binary branching with arbitrary symmetry and geometry of the branches. A difference scheme common for the whole class of models under consideration was also constructed and an algorithm was elaborated for numerical solution of the obtained system of difference equations. The suggested model allows synthetizing a variety of models of branching axons and dendrites, that promotes the possibilities of model investigation of electrotonus, propagated excitation and their interactions.
Assuntos
Axônios/fisiologia , Dendritos/fisiologia , Modelos Neurológicos , Animais , Simulação por Computador , Eletrofisiologia , Humanos , Matemática , Neurônios/fisiologiaRESUMO
Cord dorsum potentials were evoked by frequency-modulated stimulation of peripheral afferents in anesthetized cats. Amplitude changes of N1-component of these potentials were studied. The phase of amplitude oscillations was opposite to the phase of the sinusoidal modulation signal in the frequency range from 0.2 to 10.0 Hz. At the same time the amplitude of antidromic discharges in the dorsal roots evoked by stimulation of afferents in the zone of their entrance into the spinal cord was changed synphasically to the modulation signal. It is suggested that the observed changes in the N1-component of the cord dorsum potential depend mainly on variations in the level of the primary afferent depolarization.
Assuntos
Medula Espinal/fisiologia , Animais , Gatos , Estimulação Elétrica/métodos , Potenciais Evocados , Neurônios Aferentes/fisiologia , Raízes Nervosas Espinhais/fisiologia , Transmissão SinápticaRESUMO
Transmission of the reticulofugal activity via the interneurons localized in the ventromedial grey matter of the lumbar region and monosynaptically activated from the reticulospinal fibres was studied in anaesthetized immobilized cats. Interneurons usually generated stationary discharges when reticulospinal pathways were rhythmically stimulated with relatively low frequencies (up to 80-100/s); with further increase of stimulation frequency the discharges became non-stationary (initial high-frequency phase was followed by partial or complete discharge suppression). Maximal firing rate at the initial phase could not exceed 180-230 imp./s. The "transfer function" (the ratio of response frequency to stimulation frequency) reached 0.7-0.8 at low stimulation frequencies and decreased substantially at higher ones. Using mathematical modelling of the excitatory and post-activation inhibitory actions in these neurons, the parameters have been estimated which determine the transfer properties, of the interneuronal population relaying reticulofugal activity.