RESUMEN
Information transfer may not be limited only to synapses. Therefore, the processes and dynamics of biological neuron-astrocyte coupling and intercellular interaction within this domain are worth investigating. Existing models of tripartite synapse consider an astrocyte as a point process. Here, we extended the tripartite synapse model by considering the astrocytic processes (synaptic and perinodal) as compartments. The scattered extrinsic signals in the extracellular space and the presence of calcium stores in different astrocytic sites create local transient [Ca2+]. We investigated the Ca2+ dynamics and found that the increase in astrocytic intracellular [Ca2+] enhances the probability of neurotransmitter release. However, the period in which the extrasynaptic glutamate lingers in the extracellular space may cause excitotoxicity. We propose further biological investigation on intercellular communication, considering that unconventional sources (nonsynaptic) of glutamate may improve information processing in neuron-astrocyte networks.
Asunto(s)
Astrocitos/fisiología , Comunicación Celular/fisiología , Modelos Neurológicos , Sinapsis/fisiología , Algoritmos , Animales , Astrocitos/ultraestructura , Calcio/metabolismo , Señalización del Calcio/fisiología , Simulación por Computador , Espacio Extracelular/fisiología , Ácido Glutámico/fisiología , Humanos , Vaina de Mielina , Terminales Presinápticos/fisiología , Nódulos de Ranvier , Sinapsis/ultraestructura , Transmisión SinápticaRESUMEN
The Scn8amedJ mutation of the gene for sodium channels at the nodes of Ranvier slows nerve conduction, resulting in motor abnormalities. This mutation is also associated with loss of spontaneous bursting activity in the dorsal cochlear nucleus. However initial tests of auditory sensitivity in mice homozygous for this mutation, using standard 400-ms tones, demonstrated normal hearing sensitivity. Further testing, reported here, revealed a severely compromised sensitivity to short-duration tones of 10 and 2â¯ms durations. Such a deficit might be expected to interfere with auditory functions that depend on rapid processing of auditory signals.
Asunto(s)
Umbral Auditivo/fisiología , Mutación , Canal de Sodio Activado por Voltaje NAV1.6/deficiencia , Canal de Sodio Activado por Voltaje NAV1.6/genética , Estimulación Acústica , Animales , Audiometría de Tonos Puros , Núcleo Coclear/fisiopatología , Pruebas Auditivas , Homocigoto , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Mutantes , Canal de Sodio Activado por Voltaje NAV1.6/fisiología , Conducción Nerviosa/genética , Conducción Nerviosa/fisiología , Nódulos de Ranvier/fisiología , Factores de TiempoRESUMEN
The complex manifestations of chronic multiple sclerosis (MS)are due in part to widespread axonal abnormalities that affect lesional and nonlesional areas in the central nervous system. We describe an association between microglial activation and axon/oligodendrocyte pathology at nodal and paranodal domains in normal-appearing white matter (NAWM) of MS cases and in experimental autoimmune encephalomyelitis (EAE). The extent of paranodal axoglial (neurofascin-155(+)/Caspr1(+)) disruption correlated with local microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axoglial alterations were seen in the subcortical white matter of Parkinson disease cases and in preclinical EAE, at a time point when there is microglial activation before the infiltration of immune cells. Disruption of the axoglial unit in adjuvant-immunized animals was reversible and coincided with the resolution of microglial inflammation; paranodal damage and microglial inflammation persisted in chronic EAE. Axoglial integrity could be preserved by the administration of minocycline, which inhibited microglial activation, in actively immunized animals. These data indicate that, in MS NAWM, permanent disruption to axoglial domains in an environment of microglial inflammation is an early indicator of axonal injury that likely affects nerve conduction and may contribute to physiologic dysfunction.
Asunto(s)
Axones/patología , Encéfalo/patología , Microglía/patología , Microglía/fisiología , Esclerosis Múltiple/patología , Adulto , Anciano , Análisis de Varianza , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Encéfalo/metabolismo , Complejo CD3/metabolismo , Proteínas de Unión al Calcio , Caspasa 1/metabolismo , Proteínas de Unión al ADN/metabolismo , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Glicoproteínas , Antígenos HLA-DR/metabolismo , Humanos , Indoles , Canal de Potasio Kv.1.2/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos , Microglía/inmunología , Microscopía Confocal , Persona de Mediana Edad , Minociclina/farmacología , Minociclina/uso terapéutico , Glicoproteína Mielina-Oligodendrócito , Canal de Sodio Activado por Voltaje NAV1.6 , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Neurofilamentos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fragmentos de Péptidos , Cambios Post Mortem , Nódulos de Ranvier/efectos de los fármacos , Nódulos de Ranvier/metabolismo , Nódulos de Ranvier/patología , Canales de Sodio/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
On the basis of completed experimental research on intact nodes of Ranvier in isolated nerve fibres we decided that outcome in perinodal space during excitation potassium ions accumulation realized some important functions: it decreased the potassium ions outflow from axoplasma; it caused prolonged postspike depolarization; it activated action of electrogenic membranous Na-K pump; it predetermined the generation of prolonged components of posttetanic hyperpolatisation that appeared as a supplementary factor for potassium ions reabsorbing in cytoplasm; it did underlie the mechanisms of repeated and rhythmic activity and others.
Asunto(s)
Potenciales de la Membrana/fisiología , Potasio/metabolismo , Nódulos de Ranvier/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Animales , Transporte Iónico/fisiología , Rana temporariaRESUMEN
We simulated the effects of delivering focal electrical stimuli to the central nervous system to modulate the firing rate of neurons and alleviate motor disorders. Application of these stimuli to the spinal cord to reduce the increased excitability of motoneurons and resulting spasticity after spinal cord injury (SCI) was examined by means of a morphologically detailed computer model of a spinal motoneuron. High-frequency sinusoidal and rectangular pulses as well as biphasic charge-balanced and charge-imbalanced pulses were examined. Our results suggest that suprathreshold high-frequency sinusoidal or rectangular current pulses could inactivate the Na+ channels in the soma and initial segment, and block action potentials from propagating through the axon. Subthreshold biphasic charge-imbalanced pulses reduced the motoneuronal firing rate significantly (up to approximately 25% reduction). The reduction in firing rate was achieved through stimulation-induced hyperpolarization generated in the first node of Ranvier. Because of their low net DC current, these pulses could be tolerated safely by the tissue. To deliver charge-imbalanced pulses with the lowest net DC current and induce the largest reduction in motoneuronal firing rate, we studied the effect of various charge-imbalanced pulse parameters. Short pulse durations were found to induce the largest reduction in firing rate for the same net DC level. Subthreshold high-frequency sinusoidal and rectangular current pulses and low-frequency biphasic charge-balanced pulses, on the other hand, were ineffective in reducing the motoneuronal firing rate. In conclusion, the proposed electrical stimulation paradigms could provide potential rehabilitation interventions for suppressing the excitability of neurons to reduce the severity of motor disorders after injury to the central nervous system.
Asunto(s)
Simulación por Computador , Terapia por Estimulación Eléctrica/métodos , Modelos Neurológicos , Enfermedad de la Neurona Motora/terapia , Neuronas Motoras/metabolismo , Conducción Nerviosa , Sodio/metabolismo , Traumatismos de la Médula Espinal/complicaciones , Potenciales de Acción , Animales , Axones/metabolismo , Gatos , Enfermedad de la Neurona Motora/etiología , Enfermedad de la Neurona Motora/metabolismo , Enfermedad de la Neurona Motora/fisiopatología , Espasticidad Muscular/etiología , Espasticidad Muscular/metabolismo , Espasticidad Muscular/fisiopatología , Espasticidad Muscular/terapia , Nódulos de Ranvier/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Factores de TiempoRESUMEN
We have shown previously that the tissue nonspecific alkaline phosphatase (TNAP) is selectively expressed in the synaptic cleft of sensory cortical areas in adult mammals and, by using sensory deprivation, that TNAP activity depends on thalamocortical activity. We further analyzed this structural functional relationship by comparing the developmental pattern of TNAP activity to the maturation of the thalamocortical afferents in the primate brain (Callithrix jacchus). Cortical expression of alkaline phosphatase (AP) activity reflects the sequential maturation of the modality-specific sensory areas. Within the visual cortex, the regional and laminar distribution of AP correlates with the differential maturation of the magno- and parvocellular streams. AP activity, which is transiently expressed in the white matter, exhibits a complementary distributional pattern with myelin staining. Ultrastructural analysis revealed that AP activity is localized exclusively to the myelin-free axonal segments, including the node of Ranvier. It was also found that AP activity is gradually expressed in parallel with the maturation of synaptic contacts in the neuropile. These data suggest the involvement of AP, in addition to neurotransmitter synthesis previously suggested in the adult, in synaptic stabilization and in myelin pattern formation and put forward a role of AP in cortical plasticity and brain disorders.
Asunto(s)
Fosfatasa Alcalina/metabolismo , Terminales Presinápticos/enzimología , Transmisión Sináptica/fisiología , Tálamo/crecimiento & desarrollo , Corteza Visual/crecimiento & desarrollo , Vías Visuales/crecimiento & desarrollo , Envejecimiento/fisiología , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Callithrix , Diferenciación Celular/fisiología , Complejo IV de Transporte de Electrones/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Microscopía Electrónica de Transmisión , Fibras Nerviosas Mielínicas/enzimología , Fibras Nerviosas Mielínicas/ultraestructura , Neurópilo/enzimología , Neurópilo/ultraestructura , Terminales Presinápticos/ultraestructura , Nódulos de Ranvier/enzimología , Nódulos de Ranvier/ultraestructura , Sinapsis/enzimología , Sinapsis/ultraestructura , Tálamo/enzimología , Tálamo/ultraestructura , Corteza Visual/enzimología , Corteza Visual/ultraestructura , Vías Visuales/enzimología , Vías Visuales/ultraestructuraRESUMEN
The localization of the Na,K-ATPase isoenzymes in sciatic nerve remains controversial, as well as diabetes-induced changes in Na,K-ATPase isoforms. Some of these changes could be prevented by fish oil therapy. The aim of this study was to determine by confocal microscopy the distribution of Na,K-ATPase isoforms (alpha1, alpha2, alpha3, beta1, and beta2) in the sciatic nerve, the changes induced by diabetes, and the preventive effect of fish oil in diabetic neuropathy. This study was performed in three groups of rats. In the first two groups, diabetes was induced by streptozotocin and rats were supplemented daily with fish oil or olive oil at a dosage of 0.5 g/kg of body weight. The third one was a control group that was supplemented with olive oil. Five antibodies against specific epitopes of Na,K-ATPase isoenzymes were applied to stained dissociated nerve fibers with fluorescent secondary antibodies. The five isoenzymes were documented in nonspecific regions, Schwann cells (myelin), and the node of Ranvier. The localization of the alpha1, alpha2, and beta1 isoenzymes was not affected by diabetes. In contrast, diabetes induced a decrease of the alpha2 subunit (p < 0.05) and an up-regulation of the beta2 subunit (p < 0.05). These modifications were noted in both regions for alpha2 and were localized at the myelin domain only for the beta2. Fish oil supplementation prevented the diabetes-induced changes in the alpha2 subunit with an additional up-regulation. The beta2 subunit was not modified. A phenotypic change similar to nerve injury was induced by diabetes. Fish oil supplementation partially prevented some of these changes.
Asunto(s)
Diabetes Mellitus Experimental/enzimología , Aceites de Pescado/farmacología , Isoenzimas/análisis , Nervio Ciático/enzimología , ATPasa Intercambiadora de Sodio-Potasio/análisis , Animales , Anticuerpos Monoclonales , Glucemia , Peso Corporal , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/prevención & control , Inmunohistoquímica , Isoenzimas/inmunología , Masculino , Microscopía Confocal , Nódulos de Ranvier/enzimología , Ratas , Ratas Sprague-Dawley , Células de Schwann/enzimología , Nervio Ciático/citología , Nervio Ciático/efectos de los fármacos , ATPasa Intercambiadora de Sodio-Potasio/inmunologíaRESUMEN
A series of psoralens and structurally related 5,7-disubstituted coumarins was synthesized and investigated for their K+ channel blocking activity as well as for their phototoxicity to Artemia salina and their ability to generate singlet oxygen and to photomodify DNA. After screening the compounds on Ranvier nodes of the toad Xenopus laevis, the affinities of the most promising compounds, which proved to be psoralens bearing alkoxy substituents in the 5-position or alkoxymethyl substituents in the neighboring 4- or 4'-position, to a number of homomeric K+ channels were characterized. All compounds exhibited the highest affinity to Kv1.2. 5,8-Diethoxypsoralen (10d) was found to be an equally potent inhibitor of Kv1.2 and Kv1.3, while lacking the phototoxicity normally inherent in psoralens. The reported compounds represent a novel series of nonpeptide blockers of Shaker-type K+ channels that could be further developed into selective inhibitors of Kv1.2 or Kv1. 3.
Asunto(s)
Furocumarinas/síntesis química , Bloqueadores de los Canales de Potasio , Canales de Potasio , Rayos Ultravioleta , Animales , Artemia/efectos de los fármacos , Artemia/efectos de la radiación , Axones/efectos de los fármacos , Cumarinas/síntesis química , Cumarinas/farmacología , Cumarinas/toxicidad , ADN/efectos de los fármacos , ADN/metabolismo , ADN/efectos de la radiación , Evaluación Preclínica de Medicamentos , Furocumarinas/farmacología , Furocumarinas/toxicidad , Técnicas In Vitro , Oxígeno/metabolismo , Oxígeno/efectos de la radiación , Nódulos de Ranvier/efectos de los fármacos , Nódulos de Ranvier/ultraestructura , Canales de Potasio de la Superfamilia Shaker , Xenopus laevisRESUMEN
Closely related K+ channels can coassemble to form heteromultimers in expression systems, as well as in vivo. Whether in vivo this coassembly is random and inevitable or whether highly homologous channels can be segregated and targeted independently within a given cell has not been determined. In this study, we address these questions by characterizing and localizing voltage-dependent K+ channels in Schwann cells. Transcripts for three closely related members of the Shaker-like family of K+ channels are found in adult rat sciatic nerve: Kv1.1, Kv1.2, and Kv1.5. We have examined two of these and observed that both Kv1.1 and Kv1.5 proteins are expressed in Schwann cells but differ in their distributions. Kv1.5 is localized on the Schwann cell membrane at the nodes of Ranvier and in bands that run along the outer surface of the myelin. It is also seen intracellularly in the vicinity of the nucleus. Schwann cell staining for Kv1.1, on the other hand, was seen only in perinuclear, intracellular compartments. These results provide evidence that closely related channels from the same family need not coassemble and can be localized differentially in the same cell. In addition, Kv1.1 was highly concentrated in the axonal membrane at juxtaparanodal regions. The distributions of these K+ channels in myelinated nerve highlight the elaborate molecular specializations of these membranes.
Asunto(s)
Encéfalo/metabolismo , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/biosíntesis , Nódulos de Ranvier/metabolismo , Células de Schwann/metabolismo , Nervio Ciático/metabolismo , Animales , Axones/metabolismo , Axones/ultraestructura , Secuencia de Bases , Western Blotting , Encéfalo/citología , Cartilla de ADN , ADN Complementario , Expresión Génica , Biblioteca de Genes , Inmunohistoquímica , Canal de Potasio Kv.1.1 , Canal de Potasio Kv.1.2 , Canal de Potasio Kv1.5 , Microscopía Inmunoelectrónica , Datos de Secuencia Molecular , Familia de Multigenes , Vaina de Mielina/metabolismo , Canales de Potasio/análisis , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Nódulos de Ranvier/ultraestructura , Ratas , Células de Schwann/citología , Nervio Ciático/citología , Transcripción GenéticaRESUMEN
The changes in the ultrastructure of myelinic fibers of branchial plexus muscular branches have been studied during exposure to acupuncture of different duration. The studies were performed using muscular branches obtained from the forelegs of sexually mature white rats, weighing 150-170 g. The nerves were processed for electron microscopy according to a conventional technique. It is demonstrated that myelinic conductors react to the exposure by a complex of structural changes of a reactive, non-specific nature.
Asunto(s)
Terapia por Acupuntura , Plexo Braquial/ultraestructura , Músculos/inervación , Animales , Masculino , Microscopía Electrónica , Fibras Nerviosas Mielínicas/ultraestructura , Nódulos de Ranvier/ultraestructura , Ratas , Factores de TiempoRESUMEN
The dynamic response properties of the isolated frog muscle spindle receptor were investigated by recording the receptor potential evoked by pseudorandom noise (PRN) stimuli. The entire dynamic range of the receptor was determined by measuring the sensory response either at different intensities of the PRN stimulus (sigma = 8-30 microns) around a constant mean length or at the same intensity while varying the mean length from resting length L0 up to L0 + 150 microns. The 3-dB bandwidth of the test signal was 130 Hz. Random stimuli often evoked brief receptor potentials with variable size but characteristic shape. This shape contained a fast depolarization transient of the receptor potential during the stretching phase of the stimulus and a slowly decaying repolarization transient during release of stretch. The depolarization transient rose faster in proportion to the increasing amplitude of the receptor potential, so that larger receptor potentials were more phasic in character than smaller ones. The repolarization transient exhibited two segments of different exponential decay: The first brief repolarization phase lasted for 5 ms; its decline (tau = 2-5 ms) was faster for larger receptor potentials. The second slowly decaying repolarization transient was the same for different receptor potential amplitudes (tau = 47 ms). Consequently, the slow repolarization transients of succeeding receptor potentials displayed temporal summation. Since the amplitude and shape of the receptor potential remained constant during repeated sequences of PRN stimuli, this test stimulus was the most appropriate for the investigation of dynamic response properties under stationary conditions. Long-term stimulation caused a small shift of the mean membrane voltage towards hyperpolarizing values. This finding together with the marked "off effect" after termination of the stimulus indicate the action of an electrogenic pumping mechanism. The dynamic range of the muscle spindle receptor extended from resting length L0 up to L0 + 100 microns. Within this range static prestretches placed a bias upon the transducing site and effectively enhanced the amplitude of the receptor potential. Further prestretch beyond the dynamic region kept the receptor potential constant at its maximum amplitude. The receptor potential amplitude distribution was not symmetrical about the mean but was skewed in favor of depolarization values responding to the stretch trajectories of the PRN stimulus. Variation of the operating point by increasing the static prestretch also shifted the mode of the response distribution towards depolarization.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Músculos/inervación , Nódulos de Ranvier/fisiología , Estimulación Acústica , Potenciales de Acción , Animales , Potenciales Evocados , Técnicas In Vitro , Músculos/fisiología , Rana esculenta , Distribución AleatoriaRESUMEN
The functional organization of the mammalian myelinated nerve fiber is complex and elegant. In contrast to nonmyelinated axons, whose membranes have a relatively uniform structure, the mammalian myelinated axon exhibits a high degree of regional specialization that extends to the location of voltage-dependent ion channels within the axon membrane. Sodium and potassium channels are segregated into complementary membrane domains, with a distribution reflecting that of the overlying Schwann or glial cells. This complexity of organization has important implications for physiology and pathophysiology, particularly with respect to the development of myelinated fibers.
Asunto(s)
Canales Iónicos/ultraestructura , Fibras Nerviosas Mielínicas/ultraestructura , Animales , Axones/ultraestructura , Membrana Celular/ultraestructura , Técnica de Fractura por Congelación , Microscopía Electrónica , Neuroglía/ultraestructura , Potasio/metabolismo , Conejos , Nódulos de Ranvier/ultraestructura , Regeneración , Sodio/metabolismoRESUMEN
Paranodal glial loops (lateral belt cytoplasm) of myelinated CNS and PNS fibres contain tubules of agranular reticulum, as well as microtubules, wound spirally around the axon. Similar agranular elements run circumferentially in the expanded rims of sheet-like astrocytic processes encapsulating thalamic synaptic glomeruli. A role for agranular reticulum in these sites in control of the ionic composition of adjacent cellular and extracellular compartments is suggested.