Journal articles on the topic 'Spinal motoneuron'
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1
Kuo, Jason J., Martijn Schonewille, Teepu Siddique, Annet N. A. Schults, Ronggen Fu, Peter R. Bär, Roberta Anelli, C. J. Heckman, and Alfons B. A. Kroese. "Hyperexcitability of Cultured Spinal Motoneurons From Presymptomatic ALS Mice." Journal of Neurophysiology 91, no. 1 (January 2004): 571–75. http://dx.doi.org/10.1152/jn.00665.2003.
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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.
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Quinlan, K. A., E. J. Reedich, W. D. Arnold, A. C. Puritz, C. F. Cavarsan, C. J. Heckman, and C. J. DiDonato. "Hyperexcitability precedes motoneuron loss in the Smn2B/− mouse model of spinal muscular atrophy." Journal of Neurophysiology 122, no. 4 (October 1, 2019): 1297–311. http://dx.doi.org/10.1152/jn.00652.2018.
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Spinal motoneuron dysfunction and loss are pathological hallmarks of the neuromuscular disease spinal muscular atrophy (SMA). Changes in motoneuron physiological function precede cell death, but how these alterations vary with disease severity and motoneuron maturational state is unknown. To address this question, we assessed the electrophysiology and morphology of spinal motoneurons of presymptomatic Smn2B/− mice older than 1 wk of age and tracked the timing of motor unit loss in this model using motor unit number estimation (MUNE). In contrast to other commonly used SMA mouse models, Smn2B/− mice exhibit more typical postnatal development until postnatal day (P)11 or 12 and have longer survival (~3 wk of age). We demonstrate that Smn2B/− motoneuron hyperexcitability, marked by hyperpolarization of the threshold voltage for action potential firing, was present at P9–10 and preceded the loss of motor units. Using MUNE studies, we determined that motor unit loss in this mouse model occurred 2 wk after birth. Smn2B/− motoneurons were also larger in size, which may reflect compensatory changes taking place during postnatal development. This work suggests that motoneuron hyperexcitability, marked by a reduced threshold for action potential firing, is a pathological change preceding motoneuron loss that is common to multiple models of severe SMA with different motoneuron maturational states. Our results indicate voltage-gated sodium channel activity may be altered in the disease process. NEW & NOTEWORTHY Changes in spinal motoneuron physiologic function precede cell death in spinal muscular atrophy (SMA), but how they vary with maturational state and disease severity remains unknown. This study characterized motoneuron and neuromuscular electrophysiology from the Smn2B/− model of SMA. Motoneurons were hyperexcitable at postnatal day (P)9–10, and specific electrophysiological changes in Smn2B/− motoneurons preceded functional motor unit loss at P14, as determined by motor unit number estimation studies.
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Brownstone, Robert M., and Camille Lancelin. "Escape from homeostasis: spinal microcircuits and progression of amyotrophic lateral sclerosis." Journal of Neurophysiology 119, no. 5 (May 1, 2018): 1782–94. http://dx.doi.org/10.1152/jn.00331.2017.
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In amyotrophic lateral sclerosis (ALS), loss of motoneuron function leads to weakness and, ultimately, respiratory failure and death. Regardless of the initial pathogenic factors, motoneuron loss follows a specific pattern: the largest α-motoneurons die before smaller α-motoneurons, and γ-motoneurons are spared. In this article, we examine how homeostatic responses to this orderly progression could lead to local microcircuit dysfunction that in turn propagates motoneuron dysfunction and death. We first review motoneuron diversity and the principle of α-γ coactivation and then discuss two specific spinal motoneuron microcircuits: those involving proprioceptive afferents and those involving Renshaw cells. Next, we propose that the overall homeostatic response of the nervous system is aimed at maintaining force output. Thus motoneuron degeneration would lead to an increase in inputs to motoneurons, and, because of the pattern of neuronal degeneration, would result in an imbalance in local microcircuit activity that would overwhelm initial homeostatic responses. We suggest that this activity would ultimately lead to excitotoxicity of motoneurons, which would hasten the progression of disease. Finally, we propose that should this be the case, new therapies targeted toward microcircuit dysfunction could slow the course of ALS.
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Iwagaki, Noboru, and Gareth B. Miles. "Activation of group I metabotropic glutamate receptors modulates locomotor-related motoneuron output in mice." Journal of Neurophysiology 105, no. 5 (May 2011): 2108–20. http://dx.doi.org/10.1152/jn.01037.2010.
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Fast glutamatergic transmission via ionotropic receptors is critical for the generation of locomotion by spinal motor networks. In addition, glutamate can act via metabotropic glutamate receptors (mGluRs) to modulate the timing of ongoing locomotor activity. In the present study, we investigated whether mGluRs also modulate the intensity of motor output generated by spinal motor networks. Application of the group I mGluR agonist ( S)-3,5-dihydroxyphenylglycine (DHPG) reduced the amplitude and increased the frequency of locomotor-related motoneuron output recorded from the lumbar ventral roots of isolated mouse spinal cord preparations. Whole cell patch-clamp recordings of spinal motoneurons revealed multiple mechanisms by which group I mGluRs modulate motoneuron output. Although DHPG depolarized the resting membrane potential and reduced the voltage threshold for action potential generation, the activation of group I mGluRs had a net inhibitory effect on motoneuron output that appeared to reflect the modulation of fast, inactivating Na+ currents and action potential parameters. In addition, group I mGluR activation decreased the amplitude of locomotor-related excitatory input to motoneurons. Analyses of miniature excitatory postsynaptic currents indicated that mGluRs modulate synaptic drive to motoneurons via both pre- and postsynaptic mechanisms. These data highlight group I mGluRs as a potentially important source of neuromodulation within the spinal cord that, in addition to modulating components of the central pattern generator for locomotion, can modulate the intensity of motoneuron output during motor behavior. Given that group I mGluR activation reduces motoneuron excitability, mGluRs may provide negative feedback control of motoneuron output, particularly during high levels of glutamatergic stimulation.
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Li, Y., X. Li, P. J. Harvey, and D. J. Bennett. "Effects of Baclofen on Spinal Reflexes and Persistent Inward Currents in Motoneurons of Chronic Spinal Rats With Spasticity." Journal of Neurophysiology 92, no. 5 (November 2004): 2694–703. http://dx.doi.org/10.1152/jn.00164.2004.
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In the months after spinal cord injury, motoneurons develop large voltage-dependent persistent inward currents (PICs) that cause sustained reflexes and associated muscle spasms. These muscle spasms are triggered by any excitatory postsynaptic potential (EPSP) that is long enough to activate the PICs, which take >100 ms to activate. The PICs are composed of a persistent sodium current (Na PIC) and a persistent calcium current (Ca PIC). Considering that Ca PICs have been shown in other neurons to be inhibited by baclofen, we tested whether part of the antispastic action of baclofen was to reduce the motoneuron PICs as opposed to EPSPs. The whole sacrocaudal spinal cord from acute spinal rats and spastic chronic spinal rats (with sacral spinal transection 2 mo previously) was studied in vitro. Ventral root reflexes were recorded in response to dorsal root stimulation. Intracellular recordings were made from motoneurons, and slow voltage ramps were used to measure PICs. Chronic spinal rats exhibited large monosynaptic and long-lasting polysynaptic ventral root reflexes, and motoneurons had associated large EPSPs and PICs. Baclofen inhibited these reflexes at very low doses with a 50% inhibition (EC50) of the mono- and polysynaptic reflexes at 0.26 ± 0.07and 0.25 ± 0.09 (SD) μM, respectively. Baclofen inhibited the monosynaptic reflex in acute spinal rats at even lower doses (EC50 = 0.18 ± 0.02 μM). In chronic (and acute) spinal rats, all reflexes and EPSPs were eliminated with 1 μM baclofen with little change in motoneuron properties (PICs, input resistance, etc), suggesting that baclofen's antispastic action is presynaptic to the motoneuron. Unexpectedly, in chronic spinal rats higher doses of baclofen (20–30 μM) significantly increased the total motoneuron PIC by 31.6 ± 12.4%. However, the Ca PIC component (measured in TTX to block the Na PIC) was significantly reduced by baclofen. Thus baclofen increased the Na PIC and decreased the Ca PIC with a net increase in total PIC. By contrast, when a PIC was induced by 5-HT (10–30 μM) in motoneurons of acute spinal rats, baclofen (20–30 μM) significantly decreased the PIC by 38.8 ± 25.8%, primarily due to a reduction in the Ca PIC (measured in TTX), which dominated the total PIC in these acute spinal neurons. In summary, baclofen does not exert its antispastic action postsynaptically at clinically achievable doses (<1 μM), and at higher doses (10–30 μM), baclofen unexpectedly increases motoneuron excitability (Na PIC) in chronic spinal rats.
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Daló, N. L., J. C. Hackman, K. Storey, and R. A. Davidoff. "Changes in motoneuron membrane potential and reflex activity induced by sudden cooling of isolated spinal cords: differences among cold-sensitive, cold-resistant and freeze-tolerant amphibian species." Journal of Experimental Biology 198, no. 8 (August 1, 1995): 1765–74. http://dx.doi.org/10.1242/jeb.198.8.1765.
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The effects of sudden cooling of the spinal cord were studied in three species of amphibians--a cold-sensitive tropical toad (Bufo marinus), a cold-resistant, aquatic, hibernating frog (Rana pipiens, northern leopard frog) and a freeze-tolerant frog (Rana sylvatica, wood frog). Ventral root (motoneuron) potentials were recorded from isolated, hemisected spinal cords of each species mounted in a sucrose-gap recording apparatus and superfused with HCO3(-)-buffered Ringer's solution at room temperature (21 degrees C). In the toad, sudden cooling to 6-8 degrees C produced large, sustained motoneuron depolarizations that returned slowly to baseline levels and were accompanied by extensive paroxysmal activity. Larger, but shorter-lasting, motoneuron depolarizations associated with only a limited amount of paroxysmal activity were generated by rapid cooling of the leopard frog spinal cord. Small, brief motoneuron depolarizations followed by a hyperpolarization, or hyperpolarizations not preceded by depolarizations, were seen in cooled wood frog spinal cords. The wood frog displayed a large amount of spontaneous motoneuron activity, but little paroxysmal activity in response to sudden cooling. Following prolonged cooling, rewarming the spinal cords of all three species resulted in motoneuron hyperpolarizations that slowly decayed towards the baseline value. The amplitude of the rewarming-induced response was larger and longer in toad motoneurons than in leopard frog and wood frog motoneurons. At room temperature, a single supramaximal dorsal root stimulus evoked a depolarizing ventral root potential in toad and leopard frog motoneurons that was decreased in amplitude and prolonged when the spinal cords were cooled to 8 degrees C or below. In contrast, at room temperature, the ventral root reflex in the wood frog was followed by a distinct hyperpolarization. Cooling the wood frog spinal cord only slightly reduced the amplitude of the ventral root potential. In contrast, the evoked hyperpolarization was blocked by sudden cooling and also by the addition of dihydro-ouabain to the Ringer's solution. The motoneuron hyperpolarizations induced by sudden cooling in the wood frog were converted to depolarizations when Cl- in the superfusate was replaced with isethionate. The depolarizations elicited by sudden cooling were reduced by the addition of kynurenate in all three species. A dose-response curve generated by short applications of L-glutamate demonstrated that wood frog motoneurons were less sensitive than leopard frog motoneurons to L-glutamate. In summary, three species of amphibians, differing in their adaptations to the temperature of their environments, vary in their responses to sudden reductions in temperature. The relationship of these responses to their environmental adaptations remains to be determined.
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Hochman, S., and D. A. McCrea. "Effects of chronic spinalization on ankle extensor motoneurons. I. Composite monosynaptic Ia EPSPs in four motoneuron pools." Journal of Neurophysiology 71, no. 4 (April 1, 1994): 1452–67. http://dx.doi.org/10.1152/jn.1994.71.4.1452.
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1. We examined the effects of 6-wk chronic spinalization at the L1-L2 level on composite monosynaptic Ia excitatory postsynaptic potentials (EPSPs) recorded in medial gastrocnemius (MG), lateral gastrocnemius (LG), soleus (SOL), and plantaris (PL) motoneurons. Amplitudes, rise times, and half-widths of composite monosynaptic Ia EPSPs evoked by low-strength electrical stimulation of peripheral nerves were measured in barbiturate-anesthetized cats and compared between unlesioned and chronic spinal preparations. 2. The mean amplitude of homonymous composite Ia EPSPs evoked by 1.2 times threshold (1.2T) stimulation and recorded in all four ankle extensor motoneuron pools increased 26% in chronic spinal animals compared with unlesioned controls. There was also an increased incidence of large-amplitude, short-rise time EPSPs. When the same data were separated according to individual motoneuron species, homonymous EPSP amplitudes in MG motoneurons were found to be unchanged. EPSPs recorded in LG motoneurons and evoked by stimulation of the combined LG and SOL nerve were increased by 46%. Mean EPSP amplitudes recorded in both SOL and PL motoneurons were larger after spinalization but statistical significance was only achieved when values from SOL and PL were combined to produce a larger sample size. 3. In LG motoneurons from chronic spinal animals, all EPSPs evoked by 1.2T stimulation of the LGS nerve were > or = 0.5 mV in amplitude. In unlesioned preparations, one fourth of the LG cells had EPSPs that were < or = 0.2 mV. 4. The mean amplitude of heteronymous EPSPs evoked by 2T stimulation of LGS and MG nerves and recorded in MG and LG motoneurons, respectively, doubled in size after chronic spinalization. Because homonymous EPSP amplitudes were unchanged in MG motoneurons, synaptic mechanisms and not passive membrane properties are likely responsible for increased heteronymous EPSP amplitudes in MG. 5. The mean 10-90% rise time of homonymous composite Ia EPSPs in pooled data from all motoneurons decreased 21% in 6-wk chronic spinal animals. Unlike EPSP amplitude, significant rise time decreases were found in all four motoneuron pools. Compared with the other motoneuron species, the mean homonymous rise time recorded in MG motoneurons was shortest and decreased the least in chronic spinal animals. Rise times of heteronymous Ia EPSPs in MG and LG motoneurons also decreased. The maximum rate of rise of homonymous EPSPs increased in all four motoneuron species. 6. The mean half-widths of Ia composite EPSPs decreased in 6-wk spinalized preparations in all motoneuron species.(ABSTRACT TRUNCATED AT 400 WORDS)
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Maltenfort, Mitchell G., C. J. Heckman, and W. Zev Rymer. "Decorrelating Actions of Renshaw Interneurons on the Firing of Spinal Motoneurons Within a Motor Nucleus: A Simulation Study." Journal of Neurophysiology 80, no. 1 (July 1, 1998): 309–23. http://dx.doi.org/10.1152/jn.1998.80.1.309.
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Maltenfort, Mitchell G., C. J. Heckman, and W. Zev Rymer. Decorrelating actions of Renshaw interneurons on the firing of spinal motoneurons within a motor nucleus: a simulation study. J. Neurophysiol. 80: 309–323, 1998. A simulation of spinal motoneurons and Renshaw cells was constructed to examine possible functions of recurrent inhibition. Recurrent inhibitory feedback via Renshaw cells is known to be weak. In our model, consistent with this, motoneuron firing was only reduced by a few pulses per second. Our initial hypothesis was that Renshaw cells would suppress synchronous firings of motoneurons caused by shared, dynamic inputs. Each motoneuron received an identical pattern of noise in its input. Synchrony coefficients were defined as the average motoneuron population firing relative to the activity of selected reference motoneurons; positive coefficients resulted if the motoneuron population was particularly active at the same time the reference motoneuron was active. With or without recurrent inhibition, the motoneuron pools tended to show little if any synchronization. Recurrent inhibition was expected to reduce the synchrony even further. Instead, it reduced the variance of the synchrony coefficients, without a comparable effect on the average. This suggests—surprisingly—that both positive and negative correlations between motoneurons are suppressed by recurrent inhibition. In short, recurrent inhibition may operate as a negative feedback mechanism to decorrelate motoneurons linked by common inputs. A consequence of this decorrelation is the suppression of spectral activity that apparently arises from correlated motoneuron firings due to common excitatory drive. Without recurrent inhibition, the power spectrum of the total motoneuron pool firings showed a peak at a frequency corresponding to the largest measured firing rates of motoneurons in the pool. Recurrent inhibition either reduced or abolished this peak, presumably by minimizing the likelihood of correlated firing among pool elements. Renshaw cells may act to diminish physiological tremor, by removing oscillatory components from aggregate motoneuron activity. Recurrent inhibition also improved coherence between the aggregate motoneuron output and the common drive, at frequencies above the frequency of the “synchronous” peak. Sensitivity analyses demonstrated that the spectral effect became stronger as the duration of inhibitory synaptic conductance was shortened with either the magnitude or the spatial extent of the inhibitory conductances increased to maintain constant net inhibition. Overall, Renshaw inhibition appears to be a powerful way to adjust the dynamic behavior of a neuron population with minimal impact on its static gain.
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Yamamoto, Y., J. Livet, R. A. Pollock, A. Garces, V. Arce, O. deLapeyriere, and C. E. Henderson. "Hepatocyte growth factor (HGF/SF) is a muscle-derived survival factor for a subpopulation of embryonic motoneurons." Development 124, no. 15 (August 1, 1997): 2903–13. http://dx.doi.org/10.1242/dev.124.15.2903.
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Muscle-derived factors are known to be important for the survival of developing spinal motoneurons, but the molecules involved have not been characterized. Hepatocyte growth factor/scatter factor (HGF/SF) plays an important role in muscle development and motoneuron axon outgrowth. We show that HGF/SF has potent neurotrophic activity (EC50=2 pM) for a subpopulation (40%) of purified embryonic rat motoneurons. Moreover, HGF/SF is an essential component of muscle-derived support for motoneurons, since blocking antibodies to HGF/SF specifically inhibited 65% of the trophic activity of media conditioned by C2/C7 skeletal myotubes, but did not inhibit the trophic activity secreted by Schwann cell lines. High levels of expression of the HGF/SF receptor c-Met in the spinal cord are restricted to subsets of motoneurons, mainly in limb-innervating segments. Consistent with this distribution, cultured motoneurons from limb-innervating brachial and lumbar segments showed a more potent response to HGF/SF than did thoracic motoneurons. By the end of the period of motoneuron cell death, levels of c-Met mRNA in motoneurons were markedly reduced, suggesting that the effects of HGF/SF may be limited to the period of motoneuron cell death. HGF/SF may play an important role during motoneuron development as a muscle-derived survival factor for a subpopulation of limb-innervating motoneurons.
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Smith, J. C., J. J. Greer, G. S. Liu, and J. L. Feldman. "Neural mechanisms generating respiratory pattern in mammalian brain stem-spinal cord in vitro. I. Spatiotemporal patterns of motor and medullary neuron activity." Journal of Neurophysiology 64, no. 4 (October 1, 1990): 1149–69. http://dx.doi.org/10.1152/jn.1990.64.4.1149.
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1. An analysis of the spatial and temporal patterns of activity of neurons of the respiratory motor-pattern generation system in an in vitro neonatal rat brain stem-spinal cord preparation is presented. Impulse discharge patterns of spinal and cranial moto-neurons as well as respiratory neurons in the medulla were analyzed. Patterns of motoneuronal discharge were characterized at the population level from recordings of motor-nerve discharge and at the single-cell level from intracellular recordings. These patterns were compared to patterns generated in the neonatal rat and adult mammal in vivo to establish the correspondence between in vitro and in vivo states. 2. The in vitro system generated a complex spatiotemporal pattern of spinal and cranial motoneuron activity during inspiratory (I) and expiratory (E) phases of the respiratory cycle. The respiratory cycle consisted of three distinct phases of neuronal activity (I, early E, and late E phase) similar to the temporal organization of the cycle in the intact mammal. The spike discharge pattern of motoneurons during the I phase consisted of a rapidly peaking-slowly decrementing discharge envelope with a high degree of synchronization on a time scale of 25-50 ms (approximately 20-40 Hz). A similar pattern was generated in the neonate in vivo under conditions comparable with the in vitro state (i.e., nervous system isolated from mechanosensory afferent inputs). However, the I-phase-motoneuron discharge pattern and cycle-phase durations differed from those characteristic of the intact neonatal or adult systems in vivo. This difference could be accounted for primarily by removal of vagal mechanosensory afferent inputs. 3. The synaptic drive potentials of spinal motoneurons during the I phase in vitro consisted of a rapidly peaking-slowly decrementing potential envelope similar in shape to the spike-frequency histogram of single motoneurons and the envelope of the motoneuron-population discharge. The drive potentials had prominent high-frequency amplitude fluctuations superimposed on the slower drive-potential envelope that were temporally correlated with the generation of motoneuron action potentials. The dominant frequency components of these fast-membrane-potential oscillations (20-35 Hz) were similar to the frequency components of the amplitude fluctuations in the motoneuron-population discharge. One class of medullary neurons with I-phase discharge also exhibited a rapidly peaking-slowly decrementing pattern of impulse discharge and synaptic drive potential with similar high-frequency components.(ABSTRACT TRUNCATED AT 400 WORDS)
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Kim, Hojeong. "Impact of the localization of dendritic calcium persistent inward current on the input-output properties of spinal motoneuron pool: a computational study." Journal of Applied Physiology 123, no. 5 (November 1, 2017): 1166–87. http://dx.doi.org/10.1152/japplphysiol.00034.2017.
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The goal of this study is to investigate how the dendritic Ca-PIC location influences nonlinear input-output properties and depends on the type of motoneurons across the motoneuron pool. A model motoneuron pool consisting of 10 motoneurons was constructed using a recently developed two-compartment modeling approach that reflected key cell type-associated properties experimentally identified. The dendritic excitability and firing output depended systematically on both the PIC location and the motoneuron type. The PIC onset and offset in the current-voltage ( I–V) relationship tended to occur at more hyperpolarized voltages as the path length to the PIC channels from the soma increased and as the cell type shifted from high- to low-threshold motoneurons. At the same time, the firing acceleration and frequency hysteresis in the frequency-current ( F–I) relationship became faster and larger, respectively. However, the PIC onset-offset hysteresis increased as the path length and the recruitment threshold increased. Furthermore, the gain of frequency-current function before full PIC activation was larger for PIC channels located over distal dendritic regions in low- compared with high-threshold motoneurons. When compared with previously published experimental observations, the modeling concurred when Ca-PIC channels were placed closer to the soma in high- than low-threshold motoneurons in the model motoneuron pool. All of these results suggest that the negative relationship of Ca-PIC location and cell recruitment threshold may underlie the systematic variation in I–V and F–I transformation across the motoneuron pool. NEW & NOTEWORTHY How does the dendritic location of calcium persistent inward current (Ca-PIC) influence dendritic excitability and firing behavior across the spinal motoneuron pool? This issue was investigated developing a model motoneuron pool that reflected key motoneuron type-specific properties experimentally identified. The simulation results point out the negative relationship between the distance of Ca-PIC source from the soma and cell recruitment threshold as a basis underlying the systematic variation in input-output properties of motoneurons over the motoneuron pool.
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Jablonka, Sibylle, Marcus Beck, Barbara Dorothea Lechner, Christine Mayer, and Michael Sendtner. "Defective Ca2+ channel clustering in axon terminals disturbs excitability in motoneurons in spinal muscular atrophy." Journal of Cell Biology 179, no. 1 (October 8, 2007): 139–49. http://dx.doi.org/10.1083/jcb.200703187.
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Proximal spinal muscular atrophy (SMA) is a motoneuron disease for which there is currently no effective treatment. In animal models of SMA, spinal motoneurons exhibit reduced axon elongation and growth cone size. These defects correlate with reduced β-actin messenger RNA and protein levels in distal axons. We show that survival motoneuron gene (Smn)–deficient motoneurons exhibit severe defects in clustering Cav2.2 channels in axonal growth cones. These defects also correlate with a reduced frequency of local Ca2+ transients. In contrast, global spontaneous excitability measured in cell bodies and proximal axons is not reduced. Stimulation of Smn production from the transgenic SMN2 gene by cyclic adenosine monophosphate restores Cav2.2 accumulation and excitability. This may lead to the development of new therapies for SMA that are not focused on enhancing motoneuron survival but instead investigate restoration of growth cone excitability and function.
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McWhorter, Michelle L., Umrao R. Monani, Arthur H. M. Burghes, and Christine E. Beattie. "Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding." Journal of Cell Biology 162, no. 5 (September 1, 2003): 919–32. http://dx.doi.org/10.1083/jcb.200303168.
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Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by a loss of α motoneurons in the spinal cord. SMA is caused by low levels of the ubiquitously expressed survival motor neuron (Smn) protein. As it is unclear how low levels of Smn specifically affect motoneurons, we have modeled SMA in zebrafish, a vertebrate model organism with well-characterized motoneuron development. Using antisense morpholinos to reduce Smn levels throughout the entire embryo, we found motor axon–specific pathfinding defects. Reduction of Smn in individual motoneurons revealed that smn is acting cell autonomously. These results show for the first time, in vivo, that Smn functions in motor axon development and suggest that these early developmental defects may lead to subsequent motoneuron loss.
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MacDonell, C. W., D. C. Button, E. Beaumont, B. Cormery, and P. F. Gardiner. "Plasticity of rat motoneuron rhythmic firing properties with varying levels of afferent and descending inputs." Journal of Neurophysiology 107, no. 1 (January 2012): 265–72. http://dx.doi.org/10.1152/jn.00122.2011.
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Hindlimb motoneuron excitability was compared among exercise-trained (E), sedentary (S), and spinal cord transected (T) Sprague-Dawley rats by examining the slope of the frequency-current (F/I) relationship with standard intracellular recording techniques in rats anesthetized with ketamine-xylazine. The T group included spinal transected and spinal isolated rats; the E animals were either spontaneously active (exercise wheel) or treadmill trained; and rats in the S group were housed in pairs. An analysis of motoneuron initial [1st interspike interval (ISI)], early (mean of 1st three ISIs), and steady-state (mean of last 3 ISIs) discharge rate slopes resulting from increasing and decreasing 500-ms injected square-wave depolarizing current pulses was used to describe rhythmic motoneuron properties. The steepest slope occurred in the S group (55.3 ± 22.2 Hz/nA), followed by the T group (35.5 ± 15.3 Hz/nA), while the flattest slope was found in the E group (25.4 ± 10.9 Hz/nA). The steepest steady-state slope occurred in the S group but was found to be similar between the T and E groups. Furthermore, a spike-frequency adaptation (SFA) index revealed a slower adaptation in motoneurons of the E animals only (∼40% lower). Finally, evidence for a secondary range of firing existed more frequently in the T group (41%) compared with the S (12%) and E (31%) groups. The lower F/I slope and lower SFA index of motoneurons for E rats may be a result of an increase in Na+ conductance at the initial segment. The results show that motoneuronal rhythmic firing behavior is plastic, depending on the volume of daily activation and on intact descending pathways.
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Powers, R. K., and W. Z. Rymer. "Effects of acute dorsal spinal hemisection on motoneuron discharge in the medial gastrocnemius of the decerebrate cat." Journal of Neurophysiology 59, no. 5 (May 1, 1988): 1540–56. http://dx.doi.org/10.1152/jn.1988.59.5.1540.
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1. The discharge of single alpha-motoneuron axons was recorded from small cut filaments of the medial gastrocnemius (MG) muscle nerve in the decerebrated cat preparation before and after a dorsal hemisection of the thoracic spinal cord. The remainder of the MG muscle nerve was left intact, and muscle force and multiunit electromyographic (EMG) activity were recorded along with alpha-motoneuron discharge, while motor output was varied by manual stimulation of the contralateral hindlimb. 2. We recorded activity in 32 motoneurons before and after the spinal lesion, and pre- and postlesion recruitment forces and minimum firing rates were determined for 30 of these. Postlesion decreases in minimum firing rates were observed in 25/30 motoneurons, and decreases in recruitment force were seen in 21/30 motoneurons. The remaining motoneurons, which generally had low presection recruitment forces and minimum rates, exhibited postlesion increases in both parameters (see below). 3. The effects of the spinal lesion on the recruitment force and minimum firing rate of a motoneuron were related to the prelesion values of these parameters; the largest postlesion decreases were seen in motoneurons with the highest prelesion rates and recruitment forces. Spinal lesions thus acted to shift and compress the range of recruitment forces and minimum firing rates, so that after the lesion all motoneurons tended to exhibit discharge behavior typical of that seen only in the lowest threshold motoneurons before the lesion. In addition, motoneurons with low prelesion recruitment forces (less than 1.0 N of active force) generally showed an increase in recruitment force after the lesion, indicating that the lesion may have led to changes in the prelesion recruitment order. Direct evidence of recruitment reversals was obtained in 4/14 experiments where two or more motoneurons were followed pre- and postlesion. 4. The lesion-induced changes in motoneuron discharge characteristics were associated with changes in the relations between muscle force, rectified EMG, and motoneuron rate. Postlesion discharge rates were always significantly lower than the prelesion rates when compared over the same range of EMG levels. This postlesion drop in discharge rates was generally associated with inefficient force production, as evidenced by a significant drop in muscle force for matched EMG levels. 5. The degree of discharge synchrony in MG motoneurons was assessed by calculating a spike-triggered average (STA) between axonal discharge and multiunit rectified EMG. Significant STA peaks were rare before the lesion (4/32 motoneurons) but were quite common after the lesion (29/32 motoneurons).(ABSTRACT TRUNCATED AT 400 WORDS)
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ElBasiouny, Sherif M., and Vivian K. Mushahwar. "Suppressing the excitability of spinal motoneurons by extracellularly applied electrical fields: insights from computer simulations." Journal of Applied Physiology 103, no. 5 (November 2007): 1824–36. http://dx.doi.org/10.1152/japplphysiol.00362.2007.
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The effect of extracellularly applied electrical fields on neuronal excitability and firing behavior is attributed to the interaction between neuronal morphology and the spatial distribution and level of differential polarization induced by the applied field in different elements of the neuron. The presence of voltage-gated ion channels that mediate persistent inward currents (PICs) on the dendrites of spinal motoneurons enhances the influence of electrical fields on the motoneuronal firing behavior. The goal of the present study was to investigate, with a realistic motoneuron computer model, the effects of extracellularly applied electrical fields on the excitability of spinal motoneurons with the aim of reducing the increased motoneuronal excitability after spinal cord injury (SCI). Our results suggest that electrical fields could suppress the excitability of motoneurons and reduce their firing rate significantly by modulating the magnitude of their dendritic PIC. This effect was achieved at different field directions, intensities, and polarities. The reduction in motoneuronal firing rate resulted from the reduction in the magnitude of the dendritic PIC reaching the soma by the effect of the applied electrical field. This reduction in PIC was attributed to the dendritic field-induced differential polarization and the nonlinear current-voltage relationship of the dendritic PIC-mediating channels. Because of the location of the motoneuronal somata and initial segment with respect to the dendrites, these structures were minimally polarized by the applied field compared with the extended dendrites. In conclusion, electrical fields could be used for suppressing the hyperexcitability of spinal motoneurons after SCI and reducing the level of spasticity.
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Lev-Tov, A., and M. J. O'Donovan. "Calcium imaging of motoneuron activity in the en-bloc spinal cord preparation of the neonatal rat." Journal of Neurophysiology 74, no. 3 (September 1, 1995): 1324–34. http://dx.doi.org/10.1152/jn.1995.74.3.1324.
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1. This paper describes the use of calcium imaging to monitor patterns of activity in neonatal rat motoneurons retrogradely labeled with the calcium-sensitive dye, calcium green-dextran. 2. Pressure ejection of calcium green-dextran into ventral roots and into the surgically peeled ventrolateral funiculi (VLF) at the lumbar cord labeled spinal motoneurons and interneurons. The back labeled motoneurons often formed two or three discrete clusters of cells. 3. Fluorescent changes (10-20%) could be detected in labeled motoneurons after a single antidromic stimulus of the segmental ventral root. These changes progressively increased in amplitude during stimulus trains (1-5 s) at frequencies from 5 to 50 Hz, presumably reflecting a frequency-dependent increase in free intracellular calcium. 4. Stimulation of the ipsilateral VLF at the caudal lumbar level (L6), elicited frequency-dependent, synaptically induced motoneuronal discharge. Frequency-dependent fluorescent changes could be detected in calcium green-labeled motoneurons during the VLF-induced synaptic activation. 5. The spatial spread of synaptic activity among calcium green-labeled clusters of motoneurons could be resolved after dorsal root stimulation. Low-intensity stimulation of the roots produced fluorescence changes restricted to the lateral clusters of motoneurons. With increasing stimulation intensity the fluorescence change increased in the lateral cells and could spread into the medial motoneuronal group. After a single supramaximal stimulus a similar pattern was observed with activity beginning laterally and spreading medially. 6. Substantial changes in fluorescence of calcium green-labeled motoneurons were also observed during motoneuron bursting induced by bath application of the glycine receptor antagonist strychnine or the potassium channel blocker 4-aminopyridine (4-AP). 7. Our results show that membrane-impermeant fluorescent calcium indicators can be used as a tool to study the activity of specific populations of spinal neurons during execution of motor functions in the developing mammalian spinal cord. They also suggest that lateral clusters of motoneurons in the developing spinal cord of the rat are more recruitable or excitable than more medial clusters. Further understanding of these findings requires identification of these clusters.
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Bertuzzi, Maria, Weipang Chang, and Konstantinos Ampatzis. "Adult spinal motoneurons change their neurotransmitter phenotype to control locomotion." Proceedings of the National Academy of Sciences 115, no. 42 (October 1, 2018): E9926—E9933. http://dx.doi.org/10.1073/pnas.1809050115.
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A particularly essential determinant of a neuron’s functionality is its neurotransmitter phenotype. While the prevailing view is that neurotransmitter phenotypes are fixed and determined early during development, a growing body of evidence suggests that neurons retain the ability to switch between different neurotransmitters. However, such changes are considered unlikely in motoneurons due to their crucial functional role in animals’ behavior. Here we describe the expression and dynamics of glutamatergic neurotransmission in the adult zebrafish spinal motoneuron circuit assembly. We demonstrate that part of the fast motoneurons retain the ability to switch their neurotransmitter phenotype under physiological (exercise/training) and pathophysiological (spinal cord injury) conditions to corelease glutamate in the neuromuscular junctions to enhance animals’ motor output. Our findings suggest that motoneuron neurotransmitter switching is an important plasticity-bestowing mechanism in the reconfiguration of spinal circuits that control movements.
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Bączyk, Marcin, Hanna Drzymała-Celichowska, Włodzimierz Mrówczyński, and Piotr Krutki. "Polarity-dependent adaptations of motoneuron electrophysiological properties after 5-wk transcutaneous spinal direct current stimulation in rats." Journal of Applied Physiology 129, no. 4 (October 1, 2020): 646–55. http://dx.doi.org/10.1152/japplphysiol.00301.2020.
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Transcutaneous spinal direct current stimulation applied systematically for 5 wk evoked polarity-dependent adaptations in the electrophysiological properties of rat spinal motoneurons. After anodal polarization sessions, motoneurons became more excitable and could evoke higher maximum discharge frequencies during repetitive firing than motoneurons in the sham polarization group. However, no significant adaptive changes of motoneuron properties were observed after repeated cathodal polarization in comparison with the sham control group.
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Dai, Yue, Yi Cheng, Brent Fedirchuk, Larry M. Jordan, and Junhao Chu. "Motoneuron output regulated by ionic channels: a modeling study of motoneuron frequency-current relationships during fictive locomotion." Journal of Neurophysiology 120, no. 4 (October 1, 2018): 1840–58. http://dx.doi.org/10.1152/jn.00068.2018.
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Cat lumbar motoneurons display changes in membrane properties during fictive locomotion. These changes include reduction of input resistance and afterhyperpolarization, hyperpolarization of voltage threshold, and voltage-dependent excitation of the motoneurons. The state-dependent alteration of membrane properties leads to dramatic changes in frequency-current (F-I) relationship. The mechanism underlying these changes remains unknown. Using a motoneuron model combined with electrophysiological data, we investigated the channel mechanisms underlying the regulation of motoneuronal excitability and motor output. Simulation results showed that upregulation of transient sodium, persistent sodium, or Cav1.3 calcium conductances or downregulation of calcium-activated potassium or KCNQ/Kv7 potassium conductances could increase motoneuronal excitability and motor output through hyperpolarizing (left shifting) the F-I relationships or increasing the F-I slopes, whereas downregulation of input resistance or upregulation of potassium-mediated leak conductance produced the opposite effects. The excitatory phase of locomotor drive potentials (LDPs) also substantially hyperpolarized the F-I relationships and increased the F-I slopes, whereas the inhibitory phase of the LDPs had opposite effects to a similar extent. The simulation results also showed that none of the individual channel modulations could produce all the changes in the F-I relationships. The effects of modulation of Cav1.3 and KCNQ/Kv7 on F-I relationships were supported by slice experiments with the Cav1.3 agonist Bay K8644 and the KCNQ/Kv7 antagonist XE-991. The conclusion is that the varying changes in F-I relationships during fictive locomotion could be regulated by multichannel modulations. This study provides insight into the ionic basis for control of motor output in walking. NEW & NOTEWORTHY Mammalian spinal motoneurons have their excitability adapted to facilitate recruitment and firing during locomotion. Cat lumbar motoneurons display dramatic changes in membrane properties during fictive locomotion. These changes lead to a varying alteration of frequency-current relationship. The mechanisms underlying the changes remain unknown. In particular, little is known about the ionic basis for regulation of motoneuronal excitability and thus control of the motor output for walking by the spinal motor system.
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Negro, Francesco, and Dario Farina. "Decorrelation of cortical inputs and motoneuron output." Journal of Neurophysiology 106, no. 5 (November 2011): 2688–97. http://dx.doi.org/10.1152/jn.00336.2011.
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Oscillations in the primary motor cortex are transmitted through the corticospinal tract to the motoneuron pool. This pathway is believed to produce an effective and direct command from the motor cortex to the spinal motoneurons for the modulation of the force output. In this study, we used a computational model of a population of motoneurons to investigate the factors that can influence the transmission of the cortical input to the output of motoneurons, since it can be quantified by coherence analysis. The simulations demonstrated that, despite the nonlinearity of the motoneurons, oscillations present in the cortical input are transmitted to the output of the motoneuron pool at the same frequency. However, the interference introduced by the nonlinearity of the system increases the variability of the oscillations in output, introducing spectral lines whose frequency depends on the input frequencies and the motoneuron discharge rates. Moreover, an additional source of synaptic input common to all motoneurons but independent from the corticospinal component decorrelates the cortical input and motoneuron output and, thus, decreases the magnitude of the estimated coherence, even if the effective cortical drive does not change. These results indicate that the corticospinal input can effectively be sampled by a small population of motoneurons. However, the transmission of a corticospinal drive to the motoneuron pool is influenced by the nonlinearity of the spiking processes of the active motoneurons and by synaptic inputs common to the motoneuron population but independent from the cortical input.
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Chopek, Jeremy W., Patricia C. Sheppard, Kalan Gardiner, and Phillip F. Gardiner. "Serotonin receptor and KCC2 gene expression in lumbar flexor and extensor motoneurons posttransection with and without passive cycling." Journal of Neurophysiology 113, no. 5 (March 1, 2015): 1369–76. http://dx.doi.org/10.1152/jn.00550.2014.
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Sacrocaudal motoneuron gene expression is altered following a spinal transection. Of interest here is the regulation of serotonin (5-HT) receptors (R), glutamate receptor, metabotropic 1 (mGluR1), and potassium-chloride cotransporter (KCC2), which mediate motoneuron excitability, locomotor recovery, and spasticity posttransection. The examination of these genes in lumbar motoneurons posttransection has not been studied, which is necessary for developing potential pharmacological interventions aimed at restoring locomotion and/or reducing spasticity. Also, if activity is to be used to promote recovery or reduce spasticity postinjury, a further examination of neuromuscular activity on gene expression posttransection is warranted. The purpose of this study was to examine motoneuronal gene expression of 5-HT receptors, KCC2, and mGluR1 at 3 mo following a complete thoracic spinal cord transection, with and without the inclusion of daily passive cycling. Physiological hindlimb extensor and flexor motoneurons were differentially identified with two retrograde fluorescent tracers, allowing for the identification and separate harvesting of extensor and flexor motoneurons with laser capture microdissection and the subsequent examination of mRNA content using quantitative RT-PCR analysis. We demonstrate that posttransection 5-HT1AR, 5-HT2CR, and mGluR1 expression was downregulated, whereas the 5-HT2AR was upregulated. These alterations in gene expression were observed in both flexor and extensor motoneurons, whereas passive cycling influenced gene expression in extensor but not flexor motoneurons. Passive cycling in extensor motoneurons further enhanced 5-HT2AR expression and increased 5-HT7R and KCC2 expression. Our results demonstrate that passive cycling influences serotonin receptor and KCC2 gene expression and that extensor motoneurons compared with flexor motoneurons may be more plastic to activity-based interventions posttransection.
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Giraudin, Aurore, Marie-Jeanne Cabirol-Pol, John Simmers, and Didier Morin. "Intercostal and Abdominal Respiratory Motoneurons in the Neonatal Rat Spinal Cord: Spatiotemporal Organization and Responses to Limb Afferent Stimulation." Journal of Neurophysiology 99, no. 5 (May 2008): 2626–40. http://dx.doi.org/10.1152/jn.01298.2007.
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Respiration requires the coordinated rhythmic contractions of diverse muscles to produce ventilatory movements adapted to organismal requirements. During fast locomotion, locomotory and respiratory movements are coordinated to reduce mechanical conflict between these functions. Using semi-isolated and isolated in vitro brain stem-spinal cord preparations from neonatal rats, we have characterized for the first time the respiratory patterns of all spinal intercostal and abdominal motoneurons and explored their functional relationship with limb sensory inputs. Neuroanatomical and electrophysiological procedures were initially used to locate intercostal and abdominal motoneurons in the cord. Intercostal motoneuron somata are distributed rostrocaudally from C7–T13 segments. Abdominal motoneuron somata lie between T8 and L2. In accordance with their soma distributions, inspiratory intercostal motoneurons are recruited in a rostrocaudal sequence during each respiratory cycle. Abdominal motoneurons express expiratory-related discharge that alternates with inspiration. Lesioning experiments confirmed the pontine origin of this expiratory activity, which was abolished by a brain stem transection at the rostral boundary of the VII nucleus, a critical area for respiratory rhythmogenesis. Entrainment of fictive respiratory rhythmicity in intercostal and abdominal motoneurons was elicited by periodic low-threshold dorsal root stimulation at lumbar (L2) or cervical (C7) levels. These effects are mediated by direct ascending fibers to the respiratory centers and a combination of long-projection and polysynaptic descending pathways. Therefore the isolated brain stem-spinal cord in vitro generates a complex pattern of respiratory activity in which alternating inspiratory and expiratory discharge occurs in functionally identified spinal motoneuron pools that are in turn targeted by both forelimb and hindlimb somatic afferents to promote locomotor-respiratory coupling.
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Perrins, R., and A. Roberts. "Cholinergic and electrical motoneuron-to-motoneuron synapses contribute to on-cycle excitation during swimming in Xenopus embryos." Journal of Neurophysiology 73, no. 3 (March 1, 1995): 1005–12. http://dx.doi.org/10.1152/jn.1995.73.3.1005.
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1. We have previously shown that Xenopus spinal motoneurons make both chemical and electrical synapses with neighboring motoneurons. Because motoneurons are active during swimming, these synapses would be expected to contribute excitation to their neighbors. The significance of central motoneuron to motoneuron synapses was therefore investigated by analyzing the composition of the fast on-cycle excitation underlying spiking activity during fictive swimming in spinal motoneurons. To accomplish this we developed a method for very local application of drugs around a caudal recorded neuron while still being able to evoke and record essentially unaltered fictive swimming rostrally. 2. Intracellular recordings were made from spinal motoneurons during fictive swimming. Bicuculline (40 microM) and strychnine (2 microM) were used continuously to block inhibitory potentials locally around the motoneurons. The amplitude and duration of the fast excitation underlying spiking activity was measured before and during local applications of excitatory antagonists. 3. The nicotinic antagonists d-tubocurarine (10 microM) and dihydro-beta-erythroidine (10 microM) reduced the amplitude of this excitation by approximately 20%. Nicotinic antagonists also reduced the duration of this fast on-cycle excitation. The kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) reduced the amplitude (by approximately 30%) but not the duration of the on-cycle excitation. In the presence of 100 microM Cd2+, which blocks all chemically mediated transmission, a considerable amount (50%) of on-cycle excitation remained. 4. These results suggest that 20% of the on-cycle excitation comes from activation of nicotinic receptors by naturally released acetylcholine (ACh), presumably from other motoneurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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Arvanov, Viktor L., Bradley S. Seebach, and Lorne M. Mendell. "NT-3 Evokes an LTP-Like Facilitation of AMPA/Kainate Receptor–Mediated Synaptic Transmission in the Neonatal Rat Spinal Cord." Journal of Neurophysiology 84, no. 2 (August 1, 2000): 752–58. http://dx.doi.org/10.1152/jn.2000.84.2.752.
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Neurotrophin-3 (NT-3) is a neurotrophic factor required for survival of muscle spindle afferents during prenatal development. It also acts postsynaptically to enhance the monosynaptic excitatory postsynaptic potential (EPSP) produced by these fibers in motoneurons when applied over a period of weeks to the axotomized muscle nerve in adult cats. Similar increases in the amplitude of the monosynaptic EPSP in motoneurons are observed after periodic systemic treatment of neonatal rats with NT-3. Here we show an acute action of NT-3 in enhancing the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA/kainate) receptor–mediated fast monosynaptic EPSP elicited in motoneurons by dorsal root (DR) stimulation in the in vitro hemisected neonatal rat spinal cord. The receptor tyrosine kinase inhibitor K252a blocks this action of NT-3 as does the calcium chelator bis-( o-aminophenoxy)- N, N, N′, N′-tetraacetic acid (BAPTA) injected into the motoneuron. The effect of NT-3 resembles long-term potentiation (LTP) in that transient bath application of NT-3 to the isolated spinal cord produces a long-lasting increase in the amplitude of the monosynaptic EPSP. An additional similarity is that activation of N-methyl-d-aspartate (NMDA) receptors is required to initiate this increase but not to maintain it. The NMDA receptor blocker MK-801, introduced into the motoneuron through the recording microelectrode, blocks the effect of NT-3, indicating that NMDA receptors in the motoneuron membrane are crucial. The effect of NT-3 on motoneuron NMDA receptors is demonstrated by its enhancement of the depolarizing response of the motoneuron to bath-applied NMDA in the presence of tetrodotoxin (TTX). The potentiating effects of NT-3 do not persist beyond the first postnatal week. In addition, EPSPs with similar properties evoked in the same motoneurons by stimulation of descending fibers in the ventrolateral funiculus (VLF) are not modifiable by NT-3 even in the initial postnatal week. Thus, NT-3 produces synapse-specific and age-dependent LTP-like enhancement of AMPA/kainate receptor–mediated synaptic transmission in the spinal cord, and this action requires the availability of functional NMDA receptors in the motoneuron.
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Fyffe, R. E. "Spatial distribution of recurrent inhibitory synapses on spinal motoneurons in the cat." Journal of Neurophysiology 65, no. 5 (May 1, 1991): 1134–49. http://dx.doi.org/10.1152/jn.1991.65.5.1134.
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1. Intracellular staining of Renshaw cells and alpha motoneurons was used to determine the spatial distribution of recurrent inhibitory synapses on spinal motoneurons in the cat. In each experiment, a Renshaw cell and one or more possible target motoneurons were labeled with horseradish peroxidase after physiological identification. 2. Paris of labeled neurons were reconstructed and measured at the light microscopic level. As defined by light microscopy, presumed synaptic contacts between nine Renshaw cells and 10 postsynaptic motoneurons were observed. On average, each Renshaw cell made three synaptic contacts (range 1-9) on each motoneuron. 3. Electron microscopic confirmation of several presumed contacts provided evidence that the appositions identified by light microscopic criteria are genuine contacts between Renshaw cell boutons and the labeled motoneuron. 4. All of the identified synapses observed in these experiments were located on motoneuron dendrites, between 65 and 706 microns from the soma. Use of a simplified cable model indicated that the synapses are electrotonically close to the soma, the average location being approximately 0.25 length constants from the soma (range 0.04-0.82 lambda). 5. These observations provide direct evidence to support the hypothesis that Renshaw cell synapses on motoneurons are located on the dendrites and not on the cell body (whereas reciprocal inhibitory synapses, from Ia inhibitory interneurons, are predominantly located on the soma). The functional significance of the observed distribution of Renshaw inhibitory synapses is discussed. One possibility is that the recurrent inhibitory pathway selectively inhibits particular dendritic inputs.
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Verhovshek, Tom, Yi Cai, Mark C. Osborne, and Dale R. Sengelaub. "Androgen Regulates Brain-Derived Neurotrophic Factor in Spinal Motoneurons and Their Target Musculature." Endocrinology 151, no. 1 (January 1, 2010): 253–61. http://dx.doi.org/10.1210/en.2009-1036.
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Abstract Trophic factors maintain motoneuron morphology and function in adulthood. Brain-derived neurotrophic factor (BDNF) interacts with testosterone to maintain dendritic morphology of spinal motoneurons. In addition, testosterone regulates BDNF’s receptor (trkB) in motoneurons innervating the quadriceps muscles as well as in motoneurons of the highly androgen-sensitive spinal nucleus of the bulbocavernosus (SNB). Given these interactive effects, we examined whether androgen might also regulate BDNF in quadriceps and SNB motoneurons and their corresponding target musculature. In both motoneuron populations, castration of males reduced BDNF immunolabeling, and this effect was prevented with testosterone replacement. ELISA for BDNF in the target musculature of quadriceps (vastus lateralis, VL) and SNB (bulbocavernosus, BC) motoneurons revealed that BDNF in the VL and BC muscles was also regulated by androgen. However, although castration significantly decreased BDNF concentration in the VL muscle, BDNF concentration in the BC muscle was significantly increased in castrates. Treatment of castrated males with testosterone maintained BDNF levels at those of intact males in both sets of muscles. Together, these results demonstrate that androgens regulate BDNF in both a sexually dimorphic, highly androgen-sensitive neuromuscular system as well as a more typical somatic neuromuscular system. Furthermore, in addition to the regulation of trkB, these studies provide another possible mechanism for the interactive effects of testosterone and BDNF on motoneuron morphology. More importantly, by examining both the motoneurons and the muscles they innervate, these results demonstrate that within a neural system, BDNF levels in different components are differentially affected by androgen manipulation.
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Rank, Michelle M., Xiaole Li, David J. Bennett, and Monica A. Gorassini. "Role of Endogenous Release of Norepinephrine in Muscle Spasms After Chronic Spinal Cord Injury." Journal of Neurophysiology 97, no. 5 (May 2007): 3166–80. http://dx.doi.org/10.1152/jn.01168.2006.
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The recovery of persistent inward currents (PICs) and motoneuron excitability after chronic spinal cord transection is mediated, in part, by the development of supersensitivity to residual serotonin (5HT) below the lesion. The purpose of this paper is to investigate if, like 5HT, endogenous sources of norepinephrine (NE) facilitate motoneuron PICs after chronic spinal transection. Cutaneous-evoked reflex responses in tail muscles of awake chronic spinal rats were measured after increasing presynaptic release of NE by administration of amphetamine. An increase in long-lasting reflexes, known to be mediated by the calcium component of the PIC (CaPIC), was observed even at low doses (0.1–0.2 mg/kg) of amphetamine. These findings were repeated in a reduced S2 in vitro preparation, demonstrating that the increased long-lasting reflexes by amphetamine were neural. Under intracellular voltage clamp, amphetamine application led to a large facilitation of the motoneuron CaPIC. This indicates that the increases in long-lasting reflexes induced by amphetamine in the awake animal were, in part, due to actions directly on the motoneuron. Reflex responses in acutely spinal animals were facilitated by amphetamine similar to chronic animals but only at doses that were ten times greater than that required in chronic animals (0.2 mg/kg chronic vs. 2.0 mg/kg acute), pointing to a development of supersensitivity to endogenous NE in chronic animals. In summary, the increases in long-lasting reflexes and associated motoneuron CaPICs by amphetamine are likely due to an increased release of endogenous NE, which motoneurons become supersensitive to in the chronic stages of spinal cord injury.
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Hensel, Niko, Federica Cieri, Pamela Santonicola, Ines Tapken, Tobias Schüning, Michela Taiana, Elisa Pagliari, et al. "Impairment of the neurotrophic signaling hub B-Raf contributes to motoneuron degeneration in spinal muscular atrophy." Proceedings of the National Academy of Sciences 118, no. 18 (April 30, 2021): e2007785118. http://dx.doi.org/10.1073/pnas.2007785118.
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Spinal muscular atrophy (SMA) is a motoneuron disease caused by deletions of the Survival of Motoneuron 1 gene (SMN1) and low SMN protein levels. SMN restoration is the concept behind a number of recently approved drugs which result in impressive yet limited effects. Since SMN has already been enhanced in treated patients, complementary SMN-independent approaches are needed. Previously, a number of altered signaling pathways which regulate motoneuron degeneration have been identified as candidate targets. However, signaling pathways form networks, and their connectivity is still unknown in SMA. Here, we used presymptomatic SMA mice to elucidate the network of altered signaling in SMA. The SMA network is structured in two clusters with AKT and 14-3-3 ζ/δ in their centers. Both clusters are connected by B-Raf as a major signaling hub. The direct interaction of B-Raf with 14-3-3 ζ/δ is important for an efficient neurotrophic activation of the MEK/ERK pathway and crucial for motoneuron survival. Further analyses in SMA mice revealed that both proteins were down-regulated in motoneurons and the spinal cord with B-Raf being reduced at presymptomatic stages. Primary fibroblasts and iPSC-derived motoneurons from SMA patients both showed the same pattern of down-regulation. This mechanism is conserved across species since a Caenorhabditis elegans SMA model showed less expression of the B-Raf homolog lin-45. Accordingly, motoneuron survival was rescued by a cell autonomous lin-45 expression in a C. elegans SMA model resulting in improved motor functions. This rescue was effective even after the onset of motoneuron degeneration and mediated by the MEK/ERK pathway.
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Coque, Emmanuelle, Céline Salsac, Gabriel Espinosa-Carrasco, Béla Varga, Nicolas Degauque, Marion Cadoux, Roxane Crabé, et al. "Cytotoxic CD8+T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons." Proceedings of the National Academy of Sciences 116, no. 6 (January 23, 2019): 2312–17. http://dx.doi.org/10.1073/pnas.1815961116.
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Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4+T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8+T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8+T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8+T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1)G93Amutant decreased spinal motoneuron loss. Using motoneuron-CD8+T cell coculture systems, we found that mutant SOD1-expressing CD8+T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron andSOD1G93ACD8+T cells. Activated mutant SOD1 CD8+T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8+T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS.
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Liu, G., J. L. Feldman, and J. C. Smith. "Excitatory amino acid-mediated transmission of inspiratory drive to phrenic motoneurons." Journal of Neurophysiology 64, no. 2 (August 1, 1990): 423–36. http://dx.doi.org/10.1152/jn.1990.64.2.423.
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1. The role of excitatory amino acids (EAAs) in the bulbospinal transmission of inspiratory drive was studied by intracellular and single-electrode voltage-clamp recordings from phrenic motoneurons in the in vitro neonatal rat brain stem spinal cord. 2. In all brain stem-spinal cord preparations there were spontaneously generated rhythmic membrane depolarizations and associated spiking of phrenic motoneurons during the inspiratory phase of the respiratory cycle. The envelope of the motoneuron drive potential had a rapid onset to peak (50 ms) followed by a plateau/declining phase that lasted 400-700 ms. The peak potential was approximately 10-20 mV above base-line potential. The drive current under voltage clamp had a similar shape and duration to the drive potential with a peak current greater than 1.5 nA. 3. The involvement of EAAs in the bulbospinal transmission of inspiratory drive was demonstrated by checking the effects of various EAA receptor antagonists on the phrenic motoneuron inspiratory drive. When kynurenic acid (KYN), an antagonist acting on all three subtypes of EAA receptors, was applied to the solution bathing the spinal cord, the motoneuron action potentials were abolished, and the amplitude of inspiratory drive potential was significantly reduced. To further classify the role of the different EAA receptor subtypes in the synaptic transmission of inspiratory drive, the effects on the drive potential of either 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a specific non-N-methyl-D-aspartic acid (non-NMDA) receptor antagonist, or DL-2-amino-5-phosphonovaleric acid (AP5), DL-2-amino-7-phosphonoheptanoic acid (AP7), and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imin emaleate (MK-801), NMDA receptor antagonists, were investigated. Bath or local application of CNQX induced a dose-dependent decrease of the inspiratory drive potential without changing intrinsic motoneuron membrane properties. On the other hand, application of AP7 or MK 801 had a small effect on the inspiratory drive potential or the inspiratory drive current when the motoneuron membrane potential was clamped near end-expiratory potentials (-60 to -75 mV). 4. To establish the presence of EAA receptors on the phrenic motoneuronal membrane and to provide information on the available receptor subtypes for action of the endogenously released transmitter, we tested the effects of agonists for the major EAA receptor subtypes after blocking synaptic transmission (produced by axonal action potentials) by bath application of tetrodotoxin (TTX).(ABSTRACT TRUNCATED AT 400 WORDS)
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Redman, SJ. "Monosynaptic Transmission in the Spinal Cord." Physiology 1, no. 5 (October 1, 1986): 171–74. http://dx.doi.org/10.1152/physiologyonline.1986.1.5.171.
Full textAbstract:
The synaptic action of afferent fibers on motoneurons in the spinal cord is among the longest studied problems in the central nervous system but is still far from being fully understood. This article reports on the remarkable feat of recording from a single motoneuron activated by a single fiber, followed by labeling of both to identify unequivocally the relevant synapses.
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ElBasiouny, Sherif M., David J. Bennett, and Vivian K. Mushahwar. "Simulation of Dendritic CaV1.3 Channels in Cat Lumbar Motoneurons: Spatial Distribution." Journal of Neurophysiology 94, no. 6 (December 2005): 3961–74. http://dx.doi.org/10.1152/jn.00391.2005.
Full textAbstract:
We used computer simulations to study the dendritic spatial distribution of low voltage-activated L-type calcium (CaV1.3 type) channels, which mediate hysteretic persistent inward current (PIC) in spinal motoneurons. This study was prompted by the growing experimental evidence of the functional interactions between synaptic inputs and active conductances over the motoneuron dendritic tree. A compartmental cable model of an adult cat α-motoneuron was developed in NEURON simulation environment constituting the detailed morphology of type-identified triceps surae α-motoneuron and realistic distribution of group Ia afferent-to-motoneuron contacts. Simulations of different distributions of CaV1.3 channels were conducted and the resultant behavior was compared to experimental data. Our results suggest that CaV1.3 channels do not uniformly cover the whole motoneuron dendritic tree. Instead, their distribution is similar to that of synaptic contacts. We found that CaV1.3 channels are primarily localized to a wide intermediate band overlapping with the dendritic Ia-synaptic territory at dendritic distances of 300 to 850 μm (0.62 ± 0.21λ) from the soma in triceps surae α-motoneurons. These findings explain the functional interaction between synaptic inputs and the CaV1.3 channels over the motoneuron dendritic tree.
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Bączyk, M., H. Drzymała-Celichowska, W. Mrówczyński, and P. Krutki. "Motoneuron firing properties are modified by trans-spinal direct current stimulation in rats." Journal of Applied Physiology 126, no. 5 (May 1, 2019): 1232–41. http://dx.doi.org/10.1152/japplphysiol.00803.2018.
Full textAbstract:
Spinal polarization evoked by direct current stimulation [trans-spinal direct current stimulation (tsDCS)] is a novel method for altering spinal network excitability; however, it remains not well understood. The aim of this study was to determine whether tsDCS influences spinal motoneuron activity. Twenty Wistar rats under general pentobarbital anesthesia were subjected to 15 min anodal ( n = 10) or cathodal ( n = 10) tsDCS of 0.1 mA intensity, and the electrophysiological properties of their motoneurons were intracellularly measured before, during, and after direct current application. The major effects of anodal intervention included increased minimum firing frequency and the slope of the frequency-current ( f-I) relationship, as well as decreased rheobase and currents evoking steady-state firing (SSF). The effects of cathodal polarization included decreased maximum SSF frequency, decreased f-I slope, and decreased current evoking the maximum SSF. Notably, the majority of observed effects appeared immediately after the current onset, developed during polarization, and outlasted it for at least 15 min. Moreover, the effects of anodal polarization were generally more pronounced and uniform than those evoked by cathodal polarization. Our study is the first to present polarity-dependent, long-lasting changes in spinal motoneuron firing following tsDCS, which may aid in the development of more safe and accurate application protocols in medicine and sport. NEW & NOTEWORTHY Trans-spinal direct current stimulation induces significant polarity-dependent, long-lasting changes in the threshold and firing properties of spinal motoneurons. Anodal polarization potentiates motoneuron firing whereas cathodal polarization acts mainly toward firing inhibition. The alterations in rheobase and rhythmic firing properties are not restricted to the period of current application and can be observed long after the current offset.
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Pratt, C. A., and L. M. Jordan. "Ia inhibitory interneurons and Renshaw cells as contributors to the spinal mechanisms of fictive locomotion." Journal of Neurophysiology 57, no. 1 (January 1, 1987): 56–71. http://dx.doi.org/10.1152/jn.1987.57.1.56.
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The activity of selected single alpha-motoneurons, Renshaw cells (RCs), and Ia inhibitory interneurons (IaINs) during fictive locomotion was recorded via microelectrodes in decerebrate (precollicular-postmammillary) cats in which fictive locomotion was induced by stimulation of the mesencephalic locomotor region. The interrelationships in the timing and frequency of discharge among these three interconnected cell types were determined by comparing their averaged step cycle firing histograms, which were normalized in reference to motoneuron activity recorded in ventral root filaments. Previous findings that RCs are rhythmically active during locomotion and discharge in phase with the motoneurons from which they are excited were confirmed, and further details of the phase relationships between RC and alpha-motoneuron activity during fictive locomotion were obtained. Flexor and extensor RCs became active after the onset of flexor and extensor motoneuron activity, respectively. Maximal activity in extensor RCs occurred at the end of the extension phase coincidental with the onset of hyperpolarization and a decrease in activity in extensor motoneurons. Maximal flexor RC activity occurred during middle to late flexion and was temporally related to the onset of reduced flexor motoneuron activity. The IaINs recorded in the present experiments were rhythmically active during fictive locomotion, as previously reported. The quadriceps IaINs were mainly active during the extension phase of the step cycle, along with extensor RCs. Thus the known inhibition of quadriceps IaINs by RCs coupled to quadriceps and other extensor motoneurons is obviously not sufficient to interfere with the appropriate phasing of IaIN activity and reciprocal inhibition during fictive locomotion, as had been speculated. Most of the quadriceps IaINs analyzed exhibited a decrease in discharge frequency at the end of the extension phase of the step cycle, which was coincidental with increased rates of firing in extensor RCs. These data are consistent with the possibility that extensor RCs contribute to the reduction in quadriceps IaIN discharge at the end of the extension phase of the step cycle. The possibility that IaIN rhythmicity during fictive locomotion arises from periodic inhibition, possibly from Renshaw cells, was tested by stimulating the reciprocal inhibitory pathway throughout the fictive step cycle. The amplitude of Ia inhibitory postsynaptic potentials (IPSPs) varied significantly throughout the fictive step cycle in 14 of the 17 motoneurons tested, and, in 11 of these 14 motoneurons, the Ia IPSPs were maximal during the phase of the step cycle in which the motoneuron was most
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Maltenfort, Mitchell G., Martha L. McCurdy, Carrie A. Phillips, Vladimir V. Turkin, and Thomas M. Hamm. "Location and Magnitude of Conductance Changes Produced by Renshaw Recurrent Inhibition in Spinal Motoneurons." Journal of Neurophysiology 92, no. 3 (September 2004): 1417–32. http://dx.doi.org/10.1152/jn.00874.2003.
Full textAbstract:
The mean location of Renshaw synapses on spinal motoneurons and their synaptic conductance were estimated from changes in impedance magnitude produced by sustained recurrent inhibition. Motoneuron impedance was determined by injecting quasi-white noise current into lumbosacral motoneurons of pentobarbital-anesthetized cats. Synaptic location and conductance were estimated by comparing observed impedance changes to simulation results obtained using standard motoneuron models and compartmental models fit to each impedance function. Estimated synaptic locations ranged from 0.10 to 0.41λ, with a mean of 0.19 or 0.24λ, depending on the estimation method. Average dendritic path length was 262 μm. Average synaptic conductance was 23 to 27 nS (range: 6.7 to 57.9 nS), corresponding to conductance changes of 78 to 88% of resting membrane conductance. Estimated accuracy was supported by consistency using different estimation methods, agreement with Fyffe's 1991 morphological data, and comparisons of observed and simulated recurrent IPSP amplitudes. Synaptic location, but not synaptic conductance, was correlated with rheobase, a measure of motoneuron excitability. Synaptic conductance did not depend on synaptic location. A regression analysis demonstrated that synaptic conductance and cell impedance were the principal factors determining recurrent IPSP amplitude. Simulations using the observed values and locations of Renshaw conductance demonstrate that recurrent inhibition can require as much as an additional 14 to 18% sustained excitatory synaptic conductance to depolarize motoneurons sufficiently to activate somatic or dendritic inward currents and recruit motoneurons or amplify excitatory synaptic currents.
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Bloch-Gallego, E., I. Le Roux, A. H. Joliot, M. Volovitch, C. E. Henderson, and A. Prochiantz. "Antennapedia homeobox peptide enhances growth and branching of embryonic chicken motoneurons in vitro." Journal of Cell Biology 120, no. 2 (January 15, 1993): 485–92. http://dx.doi.org/10.1083/jcb.120.2.485.
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Spinal motoneuron development is regulated by a variety of intrinsic and extrinsic factors. Among these, a possible role for homeoproteins is suggested by their expression in the motoneuron at relatively late stages. To investigate their possible involvement in motoneuron growth, we adapted a novel technique recently developed in this laboratory, based on the ability of the 60 amino acid-long homeobox of Antennapedia (pAntp) to translocate through the neuronal membrane and to accumulate in the nucleus (Joliot, A. H., C. Pernelle, H. Deagostini-Bazin, and A. Prochiantz. 1991. Proc. Natl. Acad. Sci. USA. 88:1864-1868; Joliot, A. H., A. Triller, M. Volovitch, C. Pernelle, and A. Prochiantz. 1991. New Biol. 3:1121-1134). Motoneurons from E5 chicken spinal cord were incubated with pAntp, purified by panning on SC1 antibody and plated on polyornithine/laminin substrata without further addition of pAntp. After 24 h, neurite outgrowth was already extensive in controls. In cultures of motoneurons that had been preincubated with 10(-7) M pAntp, neurite length was doubled; a similar effect was obtained using postnatal muscle extracts. Morphological analysis using a neurofilament marker specific for axons indicated that the homeobox peptide enhances primarily axonal elongation and branching. To test the hypothesis that the biological activity of pAntp involves its specific attachment to cognate homeobox binding sites present in the genome, we generated a mutant of pAntp called pAntp40P2, that was still able to translocate through the motoneuron membrane and to reach the nucleus, but had lost the specific DNA-binding properties of the wild-type peptide. Preincubation of pAntp40P2 with purified motoneurons failed to increase neurite outgrowth. This finding raises the possibility that motoneuron growth is controlled by homeobox proteins.
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Rossoll, Wilfried, Sibylle Jablonka, Catia Andreassi, Ann-Kathrin Kröning, Kathrin Karle, Umrao R. Monani, and Michael Sendtner. "Smn, the spinal muscular atrophy–determining gene product, modulates axon growth and localization of β-actin mRNA in growth cones of motoneurons." Journal of Cell Biology 163, no. 4 (November 17, 2003): 801–12. http://dx.doi.org/10.1083/jcb.200304128.
Full textAbstract:
Spinal muscular atrophy (SMA), a common autosomal recessive form of motoneuron disease in infants and young adults, is caused by mutations in the survival motoneuron 1 (SMN1) gene. The corresponding gene product is part of a multiprotein complex involved in the assembly of spliceosomal small nuclear ribonucleoprotein complexes. It is still not understood why reduced levels of the ubiquitously expressed SMN protein specifically cause motoneuron degeneration. Here, we show that motoneurons isolated from an SMA mouse model exhibit normal survival, but reduced axon growth. Overexpression of Smn or its binding partner, heterogeneous nuclear ribonucleoprotein (hnRNP) R, promotes neurite growth in differentiating PC12 cells. Reduced axon growth in Smn-deficient motoneurons correlates with reduced β-actin protein and mRNA staining in distal axons and growth cones. We also show that hnRNP R associates with the 3′ UTR of β-actin mRNA. Together, these data suggest that a complex of Smn with its binding partner hnRNP R interacts with β-actin mRNA and translocates to axons and growth cones of motoneurons.
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Drexler, Berthold, Julia Grenz, Christian Grasshoff, and Bernd Antkowiak. "Allopregnanolone Enhances GABAergic Inhibition in Spinal Motor Networks." International Journal of Molecular Sciences 21, no. 19 (October 7, 2020): 7399. http://dx.doi.org/10.3390/ijms21197399.
Full textAbstract:
The neurosteroid allopregnanolone (ALLO) causes unconsciousness by allosteric modulation of γ-aminobutyric acid type A (GABAA) receptors, but its actions on the spinal motor networks are unknown. We are therefore testing the hypothesis that ALLO attenuates the action potential firing of spinal interneurons and motoneurons predominantly via enhancing tonic, but not synaptic GABAergic inhibition. We used video microscopy to assess motoneuron-evoked muscle activity in organotypic slice cultures prepared from the spinal cord and muscle tissue. Furthermore, we monitored GABAA receptor-mediated currents by performing whole-cell voltage-clamp recordings. We found that ALLO (100 nM) reduced the action potential firing of spinal interneurons by 27% and that of α-motoneurons by 33%. The inhibitory effects of the combination of propofol (1 µM) and ALLO on motoneuron-induced muscle contractions were additive. Moreover, ALLO evoked a tonic, GABAA receptor-mediated current (amplitude: 41 pA), without increasing phasic GABAergic transmission. Since we previously showed that at a clinically relevant concentration of 1 µM propofol enhanced phasic, but not tonic GABAergic inhibition, we conclude that ALLO and propofol target distinct subpopulations of GABAA receptors. These findings provide first evidence that the combined application of ALLO and propofol may help to reduce intraoperative movements and undesired side effects that are frequently observed under total intravenous anesthesia.
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Roberts, A., N. Dale, W. H. Evoy, and S. R. Soffe. "Synaptic potentials in motoneurons during fictive swimming in spinal Xenopus embryos." Journal of Neurophysiology 54, no. 1 (July 1, 1985): 1–10. http://dx.doi.org/10.1152/jn.1985.54.1.1.
Full textAbstract:
Embryos spinalized at the 3rd to 6th postotic myotome and immobilized in 10(-4) M tubocurarine can respond to a brief skin stimulus with motor root activity suitable for swimming. Embryos spinalized at the more caudal levels give shorter episodes of fictive swimming. We have previously described the synaptic inputs to motoneurons during fictive swimming in intact embryos (23). In the present paper we look to see if similar synaptic inputs are present in spinal embryos and are therefore spinal in origin. All motoneuron firing during fictive swimming is associated with a tonic depolarization that falls away slowly once firing stops, is increased by hyperpolarizing current, and is reduced by depolarizing current. A slow depolarizing potential evoked by lower levels of skin stimulation has similar properties and rate of fall. In 1-2 mM PDA, an excitatory amino acid antagonist, only a small remnant of the depolarization remains, and motoneuron firing stops. The NMDA antagonist 50 microM APV reduces the depolarization less but also blocks firing. Motoneurons fire one spike per swimming cycle, in phase with nearby motor root discharge. Spikes are preceded by a depolarizing prepotential. This increases with hyperpolarizing current, which can block the spike to reveal an underlying depolarizing potential. In phase with motor root discharge on the opposite side of the body, motoneurons receive a midcycle inhibitory postsynaptic potential, which increases with depolarizing current, decreases with hyperpolarizing current, and is blocked by 10(-6) M strychnine. Strychnine, 5 X 10(-7) M, leads first to broadening of motor root bursts then to loss of the alternating swimming pattern of activity, which is replaced by synchronous bursts on both sides of the body. We conclude that the synaptic inputs to motoneurons during fictive swimming in spinal embryos are very similar in properties and pharmacology to those in intact embryos. These inputs, including the tonic depolarization always associated with motoneuron firing during swimming, must be at least partly spinal in origin.
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Maltenfort, Mitchell G., and Thomas M. Hamm. "Estimation of the Electrical Parameters of Spinal Motoneurons Using Impedance Measurements." Journal of Neurophysiology 92, no. 3 (September 2004): 1433–44. http://dx.doi.org/10.1152/jn.00875.2003.
Full textAbstract:
Electrical parameters of spinal motoneurons were estimated by optimizing the parameters of motoneuron models to match experimentally determined impedance functions with those of the models. The model was described by soma area, somatic and dendritic membrane resistivities, and the diameter of an equivalent dendritic cable having a standard profile. The impedance functions of motoneurons and optimized models usually differed (rms error) by <2% of input resistance. Consistent estimates for most parameters were obtained from repeated impedance determinations in individual motoneurons; estimates of dendritic resistivity were most variable. The few cells that could not be fit well had reduced impedance phase lag consistent with dendritic penetrations. Most fits were improved by inclusion of a voltage-dependent conductance GV with time constant τV. A uniformly distributed GV with τV >5 ms provided a better fit for most cells. The magnitude of this conductance decreased with depolarization. Impedance functions of other cells were adequately fit by a passive model or by a model with a somatic GV and τV <5 ms. Most of these neurons (7/8) had resting potentials positive to −60 mV. The electrotonic parameters ρ, τ, and L, estimated from model parameters, were consistent with published distributions. Most motoneuron parameters obtained in somatic shunt and sigmoidal models were well correlated, and parameters were moderately affected by changes in dendritic profile. These results demonstrate the utility and limitations of impedance measurements for estimating motoneuron parameters and suggest that voltage-dependent conductances are a substantial component of resting electrical properties.
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Powers, R. K., F. R. Robinson, M. A. Konodi, and M. D. Binder. "Effective synaptic current can be estimated from measurements of neuronal discharge." Journal of Neurophysiology 68, no. 3 (September 1, 1992): 964–68. http://dx.doi.org/10.1152/jn.1992.68.3.964.
Full textAbstract:
1. The basic question of how motoneurons transform synaptic inputs into spike train outputs remains unresolved, despite detailed knowledge of their morphology, electrophysiology, and synaptic connectivity. We have approached this problem by making measurements of a synaptic input under steady-state conditions and combining them with quantitative assessments of their effects on the discharge rates of cat spinal motoneurons. 2. We used a modified voltage-clamp technique to measure the steady-state effective synaptic currents (IN) produced by rubrospinal input to cat triceps surae motoneurons. In the same motoneurons we measured the slope of the firing rate-injected current (f-i) relation in the primary range. We then reactivated the rubrospinal input during steady, repetitive firing to assess its effect on motoneuron discharge rate. 3. We found that changes in the steady-state discharge rate of a motoneuron produced by this synaptic input could be described simply as the product of the net effective synaptic current measured at the soma and the slope of the motoneuron's f-i relation. This expression essentially redefines synaptic efficacy in terms of a cell's basic input-output function. Further, measurements of effective synaptic current simplify the task of estimating synaptic efficacy, because detailed knowledge of neither the electrotonic architecture of the postsynaptic cell nor of the locations of the presynaptic boutons is required.
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Hochman, S., and D. A. McCrea. "Effects of chronic spinalization on ankle extensor motoneurons. II. Motoneuron electrical properties." Journal of Neurophysiology 71, no. 4 (April 1, 1994): 1468–79. http://dx.doi.org/10.1152/jn.1994.71.4.1468.
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1. Intracellular recording and stimulation techniques were used in a comparison of electrical properties of triceps surae and plantaris motoneurons between unlesioned and 6-wk chronic spinal (L1-L2) cats. The primary analysis was restricted to 195 motoneurons with action potential heights > or = 80 mV. 2. Voltage transients resulting from short-duration current pulses (0.5 ms) were used to estimate membrane time constant (tau m) and equivalent cylinder electrotonic length (L). Although L was unchanged, tau m and the equalization phase time constant were significantly lower (17%) in motoneurons from chronic spinal preparations. Estimated total cell surface area was also reduced by 11%. The incidence of sag conductances, as judged from observations of the decay of voltage transients, increased from 3% to 29% after chronic spinalization. 3. Input resistance, as measured from either the amplitude of voltage responses to long-duration (50 ms) hyperpolarizing pulses (RinL) or from the area of the short-duration current pulse-induced voltage transients, was unchanged in the chronic spinal preparation. 4. Rheobase current was unchanged but threshold voltage (V Th) was increased in chronic spinal motoneurons. Increased V Th was not a result of membrane hyperpolarization because both mean action potential height (88 mV) and resting membrane potential (70 mV) were identical in both preparations. 5. The threshold current for action potential activation by short-duration (0.5 ms) current pulses increased 28% in chronic spinal preparations. This is consistent with the increase in V Th in the same motoneurons. 6. Measured V Th was identical to that calculated from the product of RinL and rheobase in the unlesioned preparation but was significantly larger than calculated V Th in chronic spinal preparations. This may indicate an increased incidence or magnitude of subthreshold rectification processes in motoneurons from chronic spinal preparations. These results in barbiturate-anesthetized preparations suggest that ankle extensor motoneurons are less excitable in the chronic spinal state. 7. Mean afterhyperpolarization duration was 10% shorter in motoneurons from chronic spinal preparations, whereas amplitude was unchanged. 8. Electrical properties were also compared in chronic spinal and unlesioned preparations using motoneurons with action potential heights of 60-79 mV. In these motoneurons with presumably poorer impalements there were no significant differences between unlesioned and chronic spinal preparations. 9. Ia monosynaptic excitatory postsynaptic potentials (EPSPs) recorded in the same motoneurons have decreased half-widths and rise times and increased amplitudes.(ABSTRACT TRUNCATED AT 400 WORDS)
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Highlander, Morgan M., John M. Allen, and Sherif M. Elbasiouny. "Meta-analysis of biological variables’ impact on spinal motoneuron electrophysiology data." Journal of Neurophysiology 123, no. 4 (April 1, 2020): 1380–91. http://dx.doi.org/10.1152/jn.00378.2019.
Full textAbstract:
Experimental, methodological, and biological variables must be accounted for statistically to maximize accuracy and comparability of published neuroscience data. However, accounting for all variables is nigh impossible. Thus we aimed to identify particularly influential variables within published neurological data, from cat, rat, and mouse studies, via a robust statistical process. Our goal was to develop tools to improve rigor in the collection and analysis of data. We strictly constrained experimental and methodological variables and then assessed four key biological variables within motoneuron research: species, age, sex, and cell type. We quantified intraexperimental and interexperimental variances in 11 commonly reported electrophysiological properties of spinal motoneurons. We first assessed variances without accounting for biological variables and then reassessed them while accounting for all four variables. We next assessed variances with all possible combinations of these four variables. We concluded that some motoneuron properties have low intraexperimental, but high interexperimental, variance; that individual motoneuron properties are impacted differently by biological variables; and that some unexplained variances still remain. We report here the optimal combinations of biological variables to reduce interexperimental variance for all 11 parameters. We also rank each parameter by intra- and interexperimental consistency. We expect these results to assist with design of experimental and analytical methods, and to support accuracy in simulations. Furthermore, although demonstrated on spinal motoneuron electrophysiology literature, our approach is applicable to biological data from all fields of neuroscience. This approach represents an important aid to experimental design, comparison of reported data, and reduction of unexplained variance in neuroscience data. NEW & NOTEWORTHY Our meta-analysis shows the impact of species, age, sex, and cell type on lumbosacral motoneuron electrophysiological properties by thoroughly quantifying variances across literature for the first time. We quantify the variances of 11 motoneuron properties with consideration of biological variables, thus providing specific insights for motoneuron modelers and experimenters, and providing a general methodological template for the quantification of variance in neurological data with the consideration of any experimental, methodological, or biological variables of interest.
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Matise, M. P., and C. Lance-Jones. "A critical period for the specification of motor pools in the chick lumbosacral spinal cord." Development 122, no. 2 (February 1, 1996): 659–69. http://dx.doi.org/10.1242/dev.122.2.659.
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When 3–4 segments of the chick lumbosacral neural tube are reversed in the anterior-posterior axis at stage 15 (embryonic day 2.5), the spinal cord develops with a reversed organization of motoneurons projecting to individual muscles in the limb (C. Lance-Jones and L. Landmesser (1980) J. Physiol. 302, 581–602). This finding indicated that motoneuron precursors or components of their local environment were specified with respect to target by stage 15. To identify the timing of this event, we have now assessed motoneuron projections after equivalent neural tube reversals at earlier stages of development. Lumbosacral neural tube segments 1–3 (+/− one segment cranial or caudal) were reversed in the anterior-posterior axis at stages 13 and 14 (embryonic day 2). The locations of motoneurons innervating two thigh muscles, the sartorius and femorotibialis, were mapped via retrograde horseradish peroxidase labeling at stages 35–36 (embryonic days 9–10). In a sample of embryos, counts were made of the total number of motoneurons in the lateral motor columns of reversed segments. The majority of motoneurons projecting to the sartorius and femorotibialis were in a normal position within the spinal cord. Segmental differences in motor column size were also similar to normal. These observations indicate that positional cues external to the LS neural tube can affect motoneuron commitment and number at stages 13–14. Since these observations stand in contrast to results following stage 15 reversals, we conclude that regional differences related to motoneuron target identity are normally specified or stabilized within the anterior LS neural tube between stages 14 and 15. To examine the role of the notochord in this process, neural tube reversals were performed at stages 13–14 as described above, except that the underlying notochord was also reversed. Projections to the sartorius and femorotibialis muscles did not differ significantly from those in embryos with neural tube reversals alone, indicating that the notochord is not the source of cues for target identity at stages 13–14.
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Pastor, Angel M., George Z. Mentis, Rosa R. De la Cruz, Eugenia Díaz, and Roberto Navarrete. "Increased Electrotonic Coupling in Spinal Motoneurons After Transient Botulinum Neurotoxin Paralysis in the Neonatal Rat." Journal of Neurophysiology 89, no. 2 (February 1, 2003): 793–805. http://dx.doi.org/10.1152/jn.00498.2002.
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The effect of early postnatal blockade of neuromuscular transmission using botulinum neurotoxin (BoNT) type A on motoneuron gap junctional coupling was studied by means of intracellular recordings and biocytin labeling using the in vitro hemisected spinal cord preparation of neonatal rats. The somata of tibialis anterior (TA) motoneurons were retrogradely labeled at birth (P0) by intramuscular injection of fluorescent tracers. Two days later, BoNT was injected unilaterally into the TA muscle. The toxin blocked neuromuscular transmission for the period studied (P4–P7) as shown by tension recordings of the TA muscle. Retrograde horseradish peroxidase tracing in animals reared to adulthood demonstrated no significant cell death or changes in the soma size of BoNT-treated TA motoneurons. Intracellular recordings were carried out in prelabeled control and BoNT-treated TA motoneurons from P4 to P7. Graded stimulation of the ventral root at subthreshold intensities elicited short-latency depolarizing (SLD) potentials that consisted of several discrete components reflecting electrotonic coupling between two or more motoneurons. BoNT treatment produced a significant increase (67%) in the maximum amplitude of the SLD and in the number of SLD components as compared with control (3.1 ± 1.7 vs. 1.4 ± 0.7; means ± SD). The morphological correlates of electrotonic coupling were investigated at the light microscope level by studying the transfer of biocytin to other motoneurons and the putative sites of gap junctional interaction. The dye-coupled neurons clustered around the injected cell with close somato-somatic, dendro-somatic and -dendritic appositions that might represent the sites of electrotonic coupling. The size of the motoneuron cluster was, on average, 2.2 times larger after BoNT treatment. Our findings demonstrate that a short-lasting functional disconnection of motoneurons from their target muscle delays motoneuron maturation by halting the elimination of gap junctional coupling that normally occurs during early postnatal development.
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Crabé, Roxane, Franck Aimond, Philippe Gosset, Frédérique Scamps, and Cédric Raoul. "How Degeneration of Cells Surrounding Motoneurons Contributes to Amyotrophic Lateral Sclerosis." Cells 9, no. 12 (November 27, 2020): 2550. http://dx.doi.org/10.3390/cells9122550.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by the progressive degeneration of upper and lower motoneurons. Despite motoneuron death being recognized as the cardinal event of the disease, the loss of glial cells and interneurons in the brain and spinal cord accompanies and even precedes motoneuron elimination. In this review, we provide striking evidence that the degeneration of astrocytes and oligodendrocytes, in addition to inhibitory and modulatory interneurons, disrupt the functionally coherent environment of motoneurons. We discuss the extent to which the degeneration of glial cells and interneurons also contributes to the decline of the motor system. This pathogenic cellular network therefore represents a novel strategic field of therapeutic investigation.
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Nakanishi, S. T., and P. J. Whelan. "Diversification of Intrinsic Motoneuron Electrical Properties During Normal Development and Botulinum Toxin–Induced Muscle Paralysis in Early Postnatal Mice." Journal of Neurophysiology 103, no. 5 (May 2010): 2833–45. http://dx.doi.org/10.1152/jn.00022.2010.
Full textAbstract:
During early postnatal development, between birth and postnatal days 8–11, mice start to achieve weight-bearing locomotion. In association with the progression of weight-bearing locomotion there are presumed developmental changes in the intrinsic electrical properties of spinal α-motoneurons. However, these developmental changes in the properties of α-motoneuron properties have not been systematically explored in mice. Here, data are presented documenting the developmental changes of selected intrinsic motoneuron electrical properties, including statistically significant changes in action potential half-width, intrinsic excitability and diversity (quantified as coefficient of variation) of rheobase current, afterhyperpolarization half-decay time, and input resistance. In various adult mammalian preparations, the maintenance of intrinsic motoneuron electrical properties is dependent on activity and/or transmission-sensitive motoneuron–muscle interactions. In this study, we show that botulinum toxin–induced muscle paralysis led to statistically significant changes in the normal development of intrinsic motoneuron electrical properties in the postnatal mouse. This suggests that muscle activity during early neonatal life contributes to the development of normal motoneuron electrical properties.
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Ziskind-Conhaim, L., B. S. Seebach, and B. X. Gao. "Changes in serotonin-induced potentials during spinal cord development." Journal of Neurophysiology 69, no. 4 (April 1, 1993): 1338–49. http://dx.doi.org/10.1152/jn.1993.69.4.1338.
Full textAbstract:
1. Motoneuron responses to serotonin (5-hydroxytryptamine, 5-HT), and the growth pattern of 5-HT projections into the ventral horn were studied in the isolated spinal cord of embryonic and neonatal rats. 2. 5-HT projections first appeared in lumbar spinal cord at days 16-17 of gestation (E16-E17) and were localized in the lateral and ventral funiculi. By E18, the projections had grown into the ventral horn, and at 1-2 days after birth they were in close apposition to motoneuron somata. 3. At E16-E17, slow-rising depolarizing potentials of 1-4 mV were recorded intracellularly in lumbar motoneurons in response to bath application of 5-HT. These potentials were not apparent after E18; at that time 5-HT generated long-lasting depolarizations with an average amplitude of 6 mV, and an increase of 11% in membrane resistance. Starting at E18, 5-HT also induced high-frequency fast-rising potentials that were blocked by antagonists of glutamate, gamma-aminobutyric acid, and glycine. 4. Motoneuron responses to 5-HT increased significantly after birth, when 5-HT produced an average depolarization of 19 mV and repetitive firing of action potentials. 5. Tetrodotoxin and high Mg2+ did not reduce the amplitude of the long-lasting depolarizations, which suggested that they were produced by direct action of 5-HT on motoneuron membrane. 6. At all developmental ages, 5-HT reduced the amplitude of dorsal root-evoked potentials. The suppressed responses were neither due to 5-HT-induced depolarization nor the result of a decrease in motoneuron excitability. 7. The pharmacological profile of 5-HT-induced potentials was studied with the use of various agonists and antagonists of 5-HT. The findings indicated that the actions of 5-HT on spinal neurons were mediated via multiple 5-HT receptor subtypes. 8. Our results suggested that 5-HT excited spinal neurons before 5-HT projections grew into the ventral horn. The characteristics of 5-HT-induced potentials changed, however, at the time when the density of 5-HT projections increased in the motor nuclei.
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Lumbroso, S., F. Sandillon, V. Georget, JM Lobaccaro, AO Brinkmann, A. Privat, and C. Sultan. "Immunohistochemical localization and immunoblotting of androgen receptor in spinal neurons of male and female rats." European Journal of Endocrinology 134, no. 5 (May 1996): 626–32. http://dx.doi.org/10.1530/eje.0.1340626.
Full textAbstract:
Lumbroso S. Sandillon F, Georget V. Lobaccaro JM, Brinkmann AO, Privat A, Sultan C. Immunohistochemical localization and immunoblotting of androgen receptor in spinal neurons of male and female rats. Eur J Endocrinol 1996:134;626–32. ISSN 0804–4643 Androgen activity in the central nervous system, as in other tissues, is mediated by the androgen receptor. We performed the precise localization of the androgen receptor in spinal cord of male and female adult rats by immunohistochemistry using polyclonal antibodies. Light microscopy indicated immunoreactivity in the anterior horn with a strong staining in motoneurons, but staining was also observed in the posterior horn. Electron microscopy showed a predominant nuclear immunostaining. A weaker but significant immunoreactive androgen receptor was also noted in the perinuclear/ intracysternal position. Moreover, no differences were found between male and female rats. Immuno-blotting demonstrated that the androgen receptor is expressed in both ventral and dorsal spinal cord, with an apparent molecular mass identical to that noted in other androgen-dependent tissues. The expression of androgen receptor in motoneurons corroborates the role of androgens in motoneuron growth, development and regeneration and underlies the possibility that androgen receptor abnormality leads to the motoneuron degeneration observed in X-linked spinal and bulbar muscular atrophy. Charles Sultan, Unité BEDR, Hôpital Lapeyronie, 34295 Montpellier, France