scholarly journals Persistent Sodium Currents and Repetitive Firing in Motoneurons of the Sacrocaudal Spinal Cord of Adult Rats

2006 ◽  
Vol 96 (3) ◽  
pp. 1141-1157 ◽  
Author(s):  
P. J. Harvey ◽  
Y. Li ◽  
X. Li ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Input Resistance ◽  
Calcium Currents ◽  
Repetitive Firing ◽  
Resting Membrane Potential ◽  
Sodium Currents ◽  
Adult Rats ◽  
Acute Spinal Rats ◽  
Chronic Spinal Rats

Months after sacral spinal transection in rats (chronic spinal rats), motoneurons below the injury exhibit large, low-threshold persistent inward currents (PICs), composed of persistent sodium currents (Na PICs) and persistent calcium currents (Ca PICs). Here, we studied whether motoneurons of normal adult rats also exhibited Na and Ca PICs when the spinal cord was acutely transected at the sacral level (acute spinal rats) and examined the role of the Na PIC in firing behavior. Intracellular recordings were obtained from motoneurons of acute and chronic spinal rats while the whole sacrocaudal spinal cord was maintained in vitro. Compared with chronic spinal rats, motoneurons of acute spinal rats were more difficult to activate because the input resistance was 22% lower and resting membrane potential was hyperpolarized 4.1 mV further below firing threshold (−50.9 ± 6.2 mV). In acute spinal rats, during a slow voltage ramp, a PIC was activated subthreshold to the spike (at −57.2 ± 5.0 mV) and reached a peak current of 1.11 ± 1.21 nA. This PIC was less than one-half the size of that in chronic spinal rats (2.79 ± 0.94 nA) and usually was not large enough to produce bistable behavior (plateau potentials and self-sustained firing not present), unlike in chronic spinal rats. The PIC was composed of two components: a TTX-sensitive Na PIC (0.44 ± 0.36 nA) and a nimodipine-sensitive Ca PIC (0.78 ± 0.82 nA). Both were smaller than in chronic spinal rats (but with similar Na/Ca ratio). The presence of the Na PIC was critical for normal repetitive firing, because no detectable Na PIC was found in the few motoneurons that could not fire repetitively during a slow ramp current injection and motoneurons that had large Na PICs more readily produced repetitive firing and had lower minimum firing rates compared with neurons with small Na PICs. Furthermore, when the Na PIC was selectively blocked with riluzole, steady repetitive firing was eliminated, even though transient firing could be evoked on a rapid current step and the spike itself was unaffected. In summary, only small Ca and Na PICs occur in acute spinal motoneurons, but the Na PIC is essential for steady repetitive firing. We discuss how availability of monoamines may explain the variability in Na PICs and firing in the normal and spinal animals.

scholarly journals Serotonin Facilitates a Persistent Calcium Current in Motoneurons of Rats With and Without Chronic Spinal Cord Injury

2007 ◽  
Vol 97 (2) ◽  
pp. 1236-1246 ◽  
Author(s):  
X. Li ◽  
K. Murray ◽  
P. J. Harvey ◽  
E. W. Ballou ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Calcium Currents ◽  
High Dose ◽  
Chronic Injury ◽  
Persistent Inward Currents ◽  
Cord Injury ◽  
Inward Currents ◽  
Acute Spinal Rats ◽  
Chronic Spinal Rats

In the months after spinal cord transection, motoneurons in the rat spinal cord develop large persistent inward currents (PICs) that are responsible for muscle spasticity. These PICs are mediated by low-threshold TTX-sensitive sodium currents (Na PIC) and L-type calcium currents (Ca PIC). Recently, the Na PIC was shown to become supersensitive to serotonin (5-HT) after chronic injury. In the present paper, a similar change in the sensitivity of the Ca PIC to 5-HT was investigated after injury. The whole sacrocaudal spinal cord from acute spinal rats and spastic chronic spinal rats (S2 level transection 2 mo previously) was studied in vitro. Intracellular recordings were made from motoneurons and slow voltages ramps were applied to measure PICs. TTX was used to block the Na PIC. For motoneurons of chronic spinal rats, a low dose of 5-HT (1 μM) significantly lowered the threshold of the Ca PIC from −56.7 ± 6.0 to −63.1 ± 7.1 mV and increased the amplitude of the Ca PIC from 2.4 ± 1.0 to 3.0 ± 0.73 nA. Higher doses of 5-HT acted similarly. For motoneurons of acute spinal rats, low doses of 5-HT had no significant effects, whereas a high dose (about 30 μM) significantly lowered the threshold of the L-Ca PIC from −58.5 ± 14.8 to −62.5 ± 3.6 mV and increased the amplitude of the Ca PIC from 0.69 ± 1.05 to 1.27 ± 1.1 nA. Thus Ca PICs in motoneurons are about 30-fold supersensitive to 5-HT in chronic spinal rats. The 5-HT–induced facilitation of the Ca PIC was blocked by nimodipine, not by the Ih current blocker Cs+ (3 mM) or the SK current blocker apamin (0.15 μM), and it lasted for hours after the removal of 5-HT from the nCSF, even increasing initially after removing 5-HT. The effects of 5-HT make motoneurons more excitable and ultimately lead to larger, more easily activated plateaus and self-sustained firing. The supersensitivity to 5-HT suggests the small amounts of endogenous 5-HT below the injury in a chronic spinal rat may act on supersensitive receptors to produce large Ca PICs and ultimately enable muscle spasms.

scholarly journals 5-HT2 Receptor Activation Facilitates a Persistent Sodium Current and Repetitive Firing in Spinal Motoneurons of Rats With and Without Chronic Spinal Cord Injury

2006 ◽  
Vol 96 (3) ◽  
pp. 1158-1170 ◽  
Author(s):  
P. J. Harvey ◽  
X. Li ◽  
Y. Li ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Sodium Current ◽  
Receptor Activation ◽  
Repetitive Firing ◽  
Persistent Sodium Current ◽  
Spinal Motoneurons ◽  
Spinal Transection ◽  
Acute Spinal Rats ◽  
Chronic Spinal Rats

We examined the modulation of persistent inward currents (PICs) by serotonin (5-HT) in spinal motoneurons of normal and chronic spinal rats. PICs are composed of both a TTX-sensitive persistent sodium current (Na PIC) and a nimodipine-sensitive persistent calcium current (Ca PIC), and we focused on quantifying the Na PIC (and its action on the total PIC), which is known to be critical in enabling repetitive firing. Intracellular recordings were made from motoneurons of the whole sacrocaudal spinal cord of normal adult rats after the cord was acutely transected at the S2 spinal level (acute spinal rat condition), removed from the animal, and then maintained in vitro. In vitro motoneuron recordings were likewise made from rats that had a sacral spinal transection 2 mo previously (chronic spinal rats). In motoneurons from acute spinal rats, moderately high doses of 5-HT (≥10 μM), or the 5-HT2 receptor agonist DOI (≥30 μM), significantly increased the total PIC, hyperpolarized the PIC onset voltage, and hyperpolarized the spike threshold, whereas lower doses had no effect. Both 5-HT and DOI specifically increased the Na PIC portion of the total PIC (tested with nimodipine blocking the Ca PIC). Additionally, 5-HT, but not DOI, depolarized the resting membrane potential ( Vm) and increased the input resistance ( Rm) in a dose-dependent manner. Therefore 5-HT2 receptor activation facilitated the Na PIC, whereas other 5-HT receptors modulated Vm and Rm. Motoneurons of chronic spinal rats responded to 5-HT and DOI in the same way, but with larger responses and at much lower doses (0.3–1 μM), thus exhibiting a 30-fold supersensitivity to 5-HT. Specifically the Na PIC was supersensitive to 5-HT2 receptor activation with DOI. Also, Rm and Vm were supersensitive to 5-HT. Consistent with the known critical role of the Na PIC in repetitive firing, enhancement of the Na PIC by DOI or 5-HT facilitated the repetitive firing evoked by steady current injection and enabled repetitive firing in a subpopulation of motoneurons of acute spinal rats that were initially unable to produce sustained repetitive firing. We suggest that after spinal transection, residual endogenous spinal sources of 5-HT help facilitate the Na PIC and repetitive firing. With chronic injury, the developed 5-HT supersensitivity more than compensates for lost brain stem 5-HT, so that the Na PIC is large and motoneurons are very excitable, thus contributing to spasticity.

scholarly journals An In Vitro Protocol for Recording From Spinal Motoneurons of Adult Rats

2008 ◽  
Vol 100 (1) ◽  
pp. 474-481 ◽  
Author(s):  
Jonathan S. Carp ◽  
Ann M. Tennissen ◽  
Donna L. Mongeluzi ◽  
Christopher J. Dudek ◽  
Xiang Yang Chen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Action Potential ◽  
Mechanical Stability ◽  
Pharmacological Study ◽  
Input Resistance ◽  
Spinal Motoneurons ◽  
Adult Rats ◽  
Precise Control

In vitro slice preparations of CNS tissue are invaluable for studying neuronal function. However, up to now, slice protocols for adult mammal spinal motoneurons—the final common pathway for motor behaviors—have been available for only limited portions of the spinal cord. In most cases, these preparations have not been productive due to the poor viability of motoneurons in vitro. This report describes and validates a new slice protocol that for the first time provides reliable intracellular recordings from lumbar motoneurons of adult rats. The key features of this protocol are: preexposure to 100% oxygen; laminectomy prior to perfusion; anesthesia with ketamine/xylazine; embedding the spinal cord in agar prior to slicing; and, most important, brief incubation of spinal cord slices in a 30% solution of polyethylene glycol to promote resealing of the many motoneuron dendrites cut during sectioning. Together, these new features produce successful recordings in 76% of the experiments and an average action potential amplitude of 76 mV. Motoneuron properties measured in this new slice preparation (i.e., voltage and current thresholds for action potential initiation, input resistance, afterhyperpolarization size and duration, and onset and offset firing rates during current ramps) are comparable to those recorded in vivo. Given the mechanical stability and precise control over the extracellular environment afforded by an in vitro preparation, this new protocol can greatly facilitate electrophysiological and pharmacological study of these uniquely important neurons and other delicate neuronal populations in adult mammals.

Biophysical Characterization of Rat Caudal Hypothalamic Neurons: Calcium Channel Contribution to Excitability

2000 ◽  
Vol 84 (6) ◽  
pp. 2896-2903 ◽  
Author(s):  
Yi-Ping Fan ◽  
Eric M. Horn ◽  
Tony G. Waldrop
Keyword(s):  
Membrane Potential ◽  
Low Voltage ◽  
Input Resistance ◽  
Calcium Currents ◽  
Resting Membrane Potential ◽  
Calcium Dependent ◽  
Rhythmic Firing ◽  
Almost All

Neurons in the caudal hypothalamus (CH) are responsible for the modulation of various processes including respiratory and cardiovascular output. Previous results from this and other laboratories have demonstrated in vivo that these neurons have firing rhythms matched to the respiratory and cardiovascular cycles. The goal of the present study was to characterize the biophysical properties of neurons in the CH with particular emphasis in those properties responsible for rhythmic firing behavior. Whole cell, patch-clamped CH neurons displayed a resting membrane potential of −58.0 ± 1.1 mV and an input resistance of 319.3 ± 16.6 MΩ when recorded in current-clamp mode in an in vitro brain slice preparation. A large proportion of these neurons displayed postinhibitory rebound (PIR) that was dependent on the duration and magnitude of hyperpolarizing current as well as the resting membrane potential of the cell. Furthermore these neurons discharged tonically in response to a depolarizing current pulse at a depolarized resting membrane potential (more positive than −65 mV) but switched to a rapid burst of firing to the same stimulus when the resting membrane potential was lowered. The PIR observed in these neurons was calcium dependent as demonstrated by the ability to block its amplitude by perfusion of Ca2+-free bath solution or by application of Ni2+ (0.3–0.5 mM) or nifedipine (10 μM). These properties suggest that low-voltage-activated (LVA) calcium current is involved in the PIR and bursting firing of these CH neurons. In addition, high-voltage-activated calcium responses were detected after blockade of outward potassium current or in Ba2+-replacement solution. In addition, almost all of the CH neurons studied showed spike frequency adaptation that was decreased following Ca2+ removal, indicating the involvement of Ca2+-dependent K+ current ( I K,Ca) in these cells. In conclusion, CH neurons have at least two different types of calcium currents that contribute to their excitability; the dominant current is the LVA or T-type. This LVA current appears to play a significant role in the bursting characteristics that may underlie the rhythmic firing of CH neurons.

Spastic Long-Lasting Reflexes of the Chronic Spinal Rat Studied In Vitro

2004 ◽  
Vol 91 (5) ◽  
pp. 2236-2246 ◽  
Author(s):  
Y. Li ◽  
P. J. Harvey ◽  
X. Li ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Adrenergic Receptor ◽  
Dorsal Root ◽  
Low Threshold ◽  
Muscle Spasms ◽  
Ventral Roots ◽  
Acute Spinal Rats ◽  
Chronic Spinal Rats ◽  
Adrenergic Receptor Agonist

Over the months following sacral spinal cord transection in adult rats, a pronounced spasticity syndrome emerges in the affected tail musculature, where long-lasting muscle spasms can be evoked by low-threshold afferent stimulation (termed long-lasting reflex). To develop an in vitro preparation to examine the neuronal mechanisms underlying spasticity, we removed the whole sacrocaudal spinal cord of these spastic chronic spinal rats (>1 mo after S2 sacral spinal transection) and maintained it in artificial cerebral spinal fluid in a recording chamber. The ventral roots were mounted on monopolar recording electrodes in grease, and the reflex responses to dorsal root stimulation were recorded and compared with the reflexes seen in the awake chronic spinal rat. When the dorsal roots were stimulated with a single pulse, a long-lasting reflex occurred in the ventral roots, with identical characteristics to the long-lasting reflex in the awake spastic rat tail. The reflex response was low threshold ( T), short latency, long duration (∼2 s), and enhanced by repeated stimulation. Brief high-frequency stimulation trains (0.5 s, 100 Hz, 1.5 × T) evoked even longer duration responses (5–10 s), with repeated bursts of activity that were similar to the repeated muscle spasms evoked in awake rats with stimulation trains or manual skin stimulation. Stimulation of a given dorsal root evoked long-lasting reflexes in both the ipsilateral and contralateral ventral roots. Long-lasting reflexes did not occur in the sacrocaudal spinal cord of acute spinal rats (S2 transection), which is similar to the areflexia seen in awake acute spinal rats. However, long-lasting reflexes could be made to occur in the acute spinal rat by altering K+ (7 mM) or Mg2+ (0 mM) concentrations, or by application of high doses of the neuromodulators norepinephrine (NE, >20 μM) or serotonin (5-HT, >20 μM). In chronic spinal rats, much lower doses of these neuromodulators (0.1 μM) enhanced the long-lasting reflexes, suggesting a denervation supersensitivity to 5-HT and NE following injury. Higher doses of NE or 5-HT produced a paradoxical inhibition of the long-lasting reflexes. The high dose inhibition by NE was mimicked by the α2-adrenergic receptor agonist clonidine but not the α1-adrenergic receptor agonist methoxamine. In summary, the sacral spinal in vitro preparation offers a new approach to the study of spinal cord injury and analysis of antispastic drugs.

Role of Persistent Sodium and Calcium Currents in Motoneuron Firing and Spasticity in Chronic Spinal Rats

2004 ◽  
Vol 91 (2) ◽  
pp. 767-783 ◽  
Author(s):  
Yunru Li ◽  
Monica A. Gorassini ◽  
David J. Bennett
Keyword(s):  
Dorsal Root ◽  
Spinal Injury ◽  
Sodium Current ◽  
Threshold Current ◽  
Calcium Currents ◽  
Repetitive Firing ◽  
Excitatory Postsynaptic Potential ◽  
Adult Rats ◽  
Inward Currents

After chronic spinal injury, motoneurons spontaneously develop two persistent inward currents (PICs): a TTX-sensitive persistent sodium current (sodium PIC) and a nimodipine-sensitive persistent calcium current (calcium PIC). In the present paper, we examined how these PICs contributed to motoneuron firing. Adult rats were spinalized at the S2 sacral level, and after 2 months intracellular recordings were made from sacrocaudal motoneurons in vitro. The PICs and repetitive firing were measured with slow triangular voltage and current ramps, respectively. The sodium PIC was examined after blocking the calcium PIC with nimodipine (20 μM; n = 12). It was always activated subthreshold, and during current ramps in nimodipine, it produced a sodium plateau that assisted in initiating and maintaining firing (self-sustained firing). The sodium PIC oscillated off and on during firing and helped initiate each spike, and near threshold this caused abnormally slow firing (2.82 ± 1.21 Hz). A low dose of TTX (0.5 μM) blocked the sodium PIC, sodium plateau, and very slow firing prior to affecting the spike itself. The calcium PIC was estimated as the current blocked by nimodipine or current remaining in TTX (2 μM; n = 13). In 59% of motoneurons, the calcium PIC was activated subthreshold to firing and produced a plateau that assisted in initiating and sustaining firing because nimodipine significantly increased the firing threshold current and decreased the self-sustained firing. In the remaining motoneurons (41%), the calcium PIC was activated suprathreshold to firing and during current ramps did not initially affect firing but eventually was activated and caused an acceleration in firing followed by self-sustained firing, which were blocked by nimodipine. The frequency-current ( F-I) slope was 3.0 ± 1.0 Hz/nA before the calcium PIC activation (primary range), 6.3 ± 3.6 Hz/nA during the calcium PIC onset (secondary range; acceleration), and 2.1 ± 1.3 Hz/nA with the calcium PIC steadily activated (tertiary range). Nimodipine eliminated the secondary and tertiary ranges, leaving a linear F-I slope of 3.7 ± 1.0 Hz/nA. A single low-threshold shock to the dorsal root evoked a many-second-long discharge, the counterpart of a muscle spasm in the awake chronic spinal rat. This long-lasting reflex was caused by the motoneuron PICs because when the activation of the voltage-dependent PICs was prevented by hyperpolarization, the same dorsal root stimulation only produced a brief excitatory postsynaptic potential (<1 s). Both the calcium and sodium PIC were involved because nimodipine only partly reduced the reflex and there remained very slow firing mediated by the sodium PIC.

Zinc enhances GABAergic transmission in rat neocortical neurons

1993 ◽  
Vol 70 (3) ◽  
pp. 1264-1269 ◽  
Author(s):  
F. M. Zhou ◽  
J. J. Hablitz
Keyword(s):  
Action Potentials ◽  
Excitatory Amino Acid ◽  
Input Resistance ◽  
Synaptic Activity ◽  
Membrane Properties ◽  
Repetitive Firing ◽  
Resting Membrane Potential ◽  
Gamma Aminobutyric Acid ◽  
Postsynaptic Potentials

1. Intracellular recordings were made in layer II-III neurons of rat neocortical slices maintained in vitro. The effect of bath application of zinc (50-300 microM) on evoked synaptic activity and passive membrane properties was examined. 2. Excitatory postsynaptic potentials (EPSPs) mediated by N-methyl-D-aspartate (NMDA) and non-NMDA receptors were recorded in response to electrical stimulation. Zinc did not affect either type of EPSP. Resting membrane potential, repetitive firing properties, and input resistance were not altered by zinc. 3. Inhibitory postsynaptic potentials (IPSPs) were enhanced after zinc application. Zinc also induced generation of large amplitude spontaneous gamma-aminobutyric acid-A (GABAA)- and GABAB-mediated IPSPs. Postsynaptic responses to iontophoretically applied GABA were unaffected. In the presence of zinc, GABAergic synaptic potentials could result in generation of action potentials. 4. Directly evoked IPSPs recorded in the presence of the excitatory amino acid receptor blockers 6-cyano-7-nitroquinoxaline-2,3-dione and 2-amino-5-phosphonovaleric acid were enhanced by zinc. Under these conditions spontaneous IPSPs with superimposed action potentials were present. Baclofen, in the presence of zinc, reduced the amplitude of evoked IPSPs. 5. These results indicate that zinc may be an endogenously occurring neuromodulator. Zinc appears to enhance GABAergic IPSPs by increasing the excitability of inhibitory interneurons, thus resulting in increased GABA release.

Plateau Potentials in Sacrocaudal Motoneurons of Chronic Spinal Rats, Recorded In Vitro

2001 ◽  
Vol 86 (4) ◽  
pp. 1955-1971 ◽  
Author(s):  
David J. Bennett ◽  
Yunru Li ◽  
Merek Siu
Keyword(s):  
Spinal Cord ◽  
Firing Rate ◽  
Dorsal Root ◽  
Reflex Response ◽  
Plateau Potentials ◽  
Chronic Injury ◽  
Acute Spinal Rats ◽  
Chronic Spinal Rats ◽  
Root Stimulation

Intracellular recordings were made from sacrocaudal tail motoneurons of acute and chronic spinal rats to examine whether plateau potentials contribute to spasticity associated with chronic injury. The spinal cord was transected at the S2 level, causing, over time, exaggerated long-lasting reflexes (hyperreflexia) associated with a general spasticity syndrome in the tail muscles of chronic spinal rats (1–5 mo postinjury). The whole sacrocaudal spinal cord of chronic or acute spinal rats was removed and maintained in vitro in normal artificial cerebral spinal fluid (ACSF). Hyperreflexia in chronic spinal rats was verified by recording the long-lasting ventral root responses to dorsal root stimulation in vitro. The intrinsic properties of sacrocaudal motoneurons were studied using intracellular injections of slow triangular current ramps or graded current pulses. In chronic spinal rats, the current injection triggered sustained firing and an associated sustained depolarization ( plateau potential; 34/35 cells; mean, 5.5 mV; duration >5 s; normal ACSF). The threshold for plateau initiation was low and usually corresponded to an acceleration in the membrane potential just before recruitment. After recruitment and plateau activation, the firing rate changed linearly with current during the slow ramps [63% of cells had a linear frequency-current ( F-I) relation] despite the presence of the plateau. The persistent inward current ( I PIC) producing the plateau and sustained firing was estimated to be on average 0.8 nA as determined by the reduction in injected current needed to stop the sustained firing [Δ I = −0.8 ± 0.6 (SD) nA], compared with the current needed to start firing ( I = 1.7 ± 1.5 nA; 47% reduction). In motoneurons of acute spinal rats, plateaus were rarely seen (3/22), although they could be made to occur with bath application of serotonin. In motoneurons of chronic spinal rats there were no significant changes in the mean passive input resistance, rheobase or amplitude of the spike afterhyperpolarization (AHP) as compared with acute spinal rats. However, there were significant increases in AHP duration and initial firing rate at recruitment and decreases in minimum firing rate and F-I slope. We suggest that the higher initial firing rate resulted from the plateau activation at recruitment and the lower F-I slope resulted from an increase in active conductance during firing, due to I PIC. Brief dorsal root stimulation also triggered a plateau and sustained discharge (long-lasting reflexes; 2–5 s) in motoneurons of chronic (but not acute) spinal rats. When the plateau was eliminated by a hyperpolarizing current bias, the reflex response was significantly shortened (to 1 s). Thus plateaus contributed substantially to the long-lasting reflexes in vitro and therefore should contribute significantly to the corresponding exaggerated reflexes and spasticity in awake chronic spinal rats.

scholarly journals Alterations of action potentials and the localization of Nav1.6 sodium channels in spared axons after hemisection injury of the spinal cord in adult rats

2011 ◽  
Vol 105 (3) ◽  
pp. 1033-1044 ◽  
Author(s):  
Arsen S. Hunanyan ◽  
Valentina Alessi ◽  
Samik Patel ◽  
Damien D. Pearse ◽  
Gary Matthews ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sodium Channels ◽  
Action Potentials ◽  
Molecular Mechanisms ◽  
Input Resistance ◽  
Ultrastructural Changes ◽  
Resting Membrane Potential ◽  
Adult Rats ◽  
Cord Injury

Previously, we reported a pronounced reduction in transmission through surviving axons contralateral to chronic hemisection (HX) of adult rat spinal cord. To examine the cellular and molecular mechanisms responsible for this diminished transmission, we recorded intracellularly from lumbar lateral white matter axons in deeply anesthetized adult rats in vivo and measured the propagation of action potentials (APs) through rubrospinal/reticulospinal tract (RST/RtST) axons contralateral to chronic HX at T10. We found decreased excitability in these axons, manifested by an increased rheobase to trigger APs and longer latency for AP propagation passing the injury level, without significant differences in axonal resting membrane potential and input resistance. These electrophysiological changes were associated with altered spatial localization of Nav1.6 sodium channels along axons: a subset of axons contralateral to the injury exhibited a diffuse localization (>10 μm spread) of Nav1.6 channels, a pattern characteristic of demyelinated axons (Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG. Proc Natl Acad Sci USA 101: 8168–8173, 2004b). This result was substantiated by ultrastructural changes seen with electron microscopy, in which an increased number of large-caliber, demyelinated RST axons were found contralateral to the chronic HX. Therefore, an increased rheobase, pathological changes in the distribution of Nav1.6 sodium channels, and the demyelination of contralateral RST axons are likely responsible for their decreased conduction chronically after HX and thus may provide novel targets for strategies to improve function following incomplete spinal cord injury.

scholarly journals Endogenous Monoamine Receptor Activation Is Essential for Enabling Persistent Sodium Currents and Repetitive Firing in Rat Spinal Motoneurons

2006 ◽  
Vol 96 (3) ◽  
pp. 1171-1186 ◽  
Author(s):  
P. J. Harvey ◽  
X. Li ◽  
Y. Li ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Sodium Channel ◽  
Receptor Activation ◽  
Repetitive Firing ◽  
Spinal Motoneurons ◽  
Sodium Currents ◽  
Receptor Antagonists ◽  
Channel Inactivation ◽  
Chronic Spinal Rats

The spinal cord and spinal motoneurons are densely innervated by terminals of serotonin (5-HT) and norepinephrine (NE) neurons arising mostly from the brain stem, but also from intrinsic spinal neurons. Even after long-term spinal transection (chronic spinal), significant amounts (10%) of 5-HT and NE (monoamines) remain caudal to the injury. To determine the role of such endogenous monoamines, we blocked their action with monoamine receptor antagonists and measured changes in the sodium currents and firing in motoneurons. We focused on persistent sodium currents (Na PIC) and sodium spike properties because they are critical for enabling repetitive firing in motoneurons and are facilitated by monoamines. Intracellular recordings were made from motoneurons in the sacrocaudal spinal cord of normal and chronic spinal rats (2 mo postsacral transection) with the whole sacrocaudal cord acutely removed and maintained in vitro (cords from normal rats termed acute spinal). Acute and chronic spinal rats had TTX-sensitive Na PICs that were respectively 0.62 ± 0.76 and 1.60 ± 1.04 nA, with mean onset voltages of −63.0 ± 5.6 and −64.1 ± 5.4 mV, measured with slow voltage ramps. Application of 5-HT2A, 5-HT2C, and α1-NE receptor antagonists (ketanserin, RS 102221, and WB 4101, respectively) significantly reduced the Na PICs, and a combined application of these three monoamine antagonists completely eliminated the Na PIC, in both acute and chronic spinal rats. Likewise, reduction of presynaptic transmitter release (including 5-HT and NE) with long-term application of cadmium also eliminated the Na PIC. Associated with the elimination of the Na PIC in monoamine antagonists, the motoneurons lost their ability to fire during slow current ramps. At this point, the spike evoked by antidromic stimulation was not affected, suggesting that activation of the transient sodium current was not impaired. However, the spike evoked after a slow ramp depolarization was slightly reduced in height and rate-of-rise, suggesting decreased sodium channel availability as a result of increased channel inactivation. These results suggest that endogenous monoamine receptor activation is critical for enabling the Na PIC and decreasing sodium channel inactivation, ultimately enabling steady repetitive firing in both normal and chronic spinal rats.

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