RESUMEN
Throughout the mammalian spinal cord, interneurones have been shown to exhibit distinct firing patterns in response to a step of injected current. In this study of ventral horn interneurones in a thick slice preparation of the lumbar cord of 11-19-day-old-rats, four distinct firing patterns were observed and classified as repetitive-firing, repetitive/burst, initial-burst or single-spiking. The hypothesis that a persistent sodium current was the predominant determinant of cell firing behaviour was investigated. A slow voltage ramp was used to assess persistent inward currents (PICs). Cells with repetitive-firing patterns had significantly larger PICs than cells displaying repetitive/burst, initial-burst or single-spiking patterns. Repetitive-firing, repetitive/burst and initial-burst-firing cells were reduced to a single-spiking pattern with the application of riluzole, which also markedly reduced the persistent sodium current. Persistent sodium current was found to account for most of the PIC with only a small contribution from L-type calcium current. These results suggest that the persistent sodium current plays a major role in determining firing patterns in these cells.
Asunto(s)
Potenciales de Acción/fisiología , Células del Asta Anterior/fisiología , Sodio/metabolismo , Animales , Calcio/metabolismo , Canales de Calcio Tipo L/fisiología , Electrofisiología , Técnicas In Vitro , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Sodio/fisiologíaRESUMEN
Motoneurons have extensive dendritic trees that receive the numerous inputs required to produce movement. These dendrites are highly active, containing voltage-sensitive channels that generate persistent inward currents (PICs) that can enhance synaptic input 5-fold or more. However, this enhancement is proportional to the level of activity of monoaminergic inputs from the brainstem that release serotonin and noradrenalin. The higher this activity, the larger the dendritic PIC and the higher the firing rate evoked by a given amount of excitatory synaptic input. This brainstem control of motoneuron input-output gain translates directly into control of system gain of a motor pool and its muscle. Because large dendritic PICs are probably necessary for motoneurons to have sufficient gain to generate large forces, it is possible that descending monoaminergic inputs scale in proportion to voluntary force. Inhibition from sensory inputs has a strong suppressive effect on dendritic PICs: the stronger the inhibition, the smaller the PIC. Thus, local inhibitory inputs within the cord may oppose the descending monoaminergic control of PICs. Most motor behaviors evoke a mixture of excitation and inhibition (e.g., the reciprocal inhibition between antagonists). Therefore, normal joint movements may involve constant adjustment of PIC amplitude.
Asunto(s)
Dendritas/fisiología , Neuronas Motoras/fisiología , Sinapsis/fisiología , Animales , Humanos , Transmisión Sináptica/fisiologíaRESUMEN
ALS (amyotrophic lateral sclerosis) is an adult-onset and deadly neurodegenerative disease characterized by a progressive and selective loss of motoneurons. Transgenic mice overexpressing a mutated human gene (G93A) coding for the enzyme SOD1 (Cu/Zn superoxide dismutase) develop a motoneuron disease resembling ALS in humans. In this generally accepted ALS model, we tested the electrophysiological properties of individual embryonic and neonatal spinal motoneurons in culture by measuring a wide range of electrical properties influencing motoneuron excitability during current clamp. There were no differences in the motoneuron resting potential, input conductance, action potential shape, or afterhyperpolarization between G93A and control motoneurons. The relationship between the motoneuron's firing frequency and injected current (f-I relation) was altered. The slope of the f-I relation and the maximal firing rate of the G93A motoneurons were much greater than in the control motoneurons. Differences in spontaneous synaptic input were excluded as a cause of increased excitability. This finding identifies a markedly elevated intrinsic electrical excitability in cultured embryonic and neonatal mutant G93A spinal motoneurons. We conclude that the observed intrinsic motoneuron hyperexcitability is induced by the SOD1 toxic gain-of-function through an aberration in the process of action potential generation. This hyperexcitability may play a crucial role in the pathogenesis of ALS as the motoneurons were cultured from presymptomatic mice.
Asunto(s)
Esclerosis Amiotrófica Lateral/patología , Neuronas Motoras/fisiología , Médula Espinal/patología , Potenciales de Acción/fisiología , Alanina/genética , Esclerosis Amiotrófica Lateral/genética , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Impedancia Eléctrica , Estimulación Eléctrica , Embrión de Mamíferos , Glicina/genética , Técnicas In Vitro , Modelos Lineales , Ratones , Ratones Transgénicos , Superóxido Dismutasa/genética , Superóxido Dismutasa-1RESUMEN
Synaptic integration in vivo often involves activation of many afferent inputs whose firing patterns modulate over time. In spinal motoneurons, sustained excitatory inputs undergo enormous enhancement due to persistent inward currents (PICs) that are generated primarily in the dendrites and are dependent on monoaminergic neuromodulatory input from the brain stem to the spinal cord. We measured the interaction between dendritic PICs and inhibition generated by tonic electrical stimulation of nerves to antagonist muscles during voltage clamp in motoneurons in the lumbar spinal cord of the cat. Separate samples of cells were obtained for two different states of monoaminergic input: standard (provided by the decerebrate preparation, which has tonic activity in monoaminergic axons) and minimal (the chloralose anesthetized preparation, which lacks tonic monoaminergic input). In the standard state, steady inhibition that increased the input conductance of the motoneurons by an average of 38% reduced the PIC by 69%. The range of this reduction, from <10% to >100%, was proportional to the magnitude of the applied inhibition. Thus nearly linear integration of synaptic inhibition may occur in these highly active dendrites. In the minimal state, PICs were much smaller, being approximately equal to inhibition-suppressed PICs in the standard state. Inhibition did not further reduce these already small PICs. Overall, these results demonstrate that inhibition from local spinal circuits can oppose the facilitation of dendritic PICs by descending monoaminergic inputs. As a result, local inhibition may also suppress active dendritic integration of excitatory inputs.