scholarly journals Persistent Sodium and Calcium Currents Cause Plateau Potentials in Motoneurons of Chronic Spinal Rats

2003 ◽  
Vol 90 (2) ◽  
pp. 857-869 ◽  
Author(s):  
Yunru Li ◽  
David J. Bennett
Keyword(s):  
Spinal Cord ◽  
Sodium Current ◽  
Negative Slope ◽  
Primary Role ◽  
Persistent Sodium Current ◽  
Plateau Potentials ◽  
Spike Threshold ◽  
Low Threshold ◽  
Chronic Spinal Rats ◽  
Initial Peak

After chronic spinal cord injury motoneurons exhibit large plateau potentials (sustained depolarizations triggered by brief inputs) that play a primary role in the development of muscle spasms and spasticity (Bennett et al. 2001a , b ). The present study examined the voltage-gated persistent inward currents (PICs) underlying these plateaus. Adult rats were spinalized at the S2 sacral spinal level and after 2 mo, when spasticity developed, intracellular recordings were made from motoneurons below the injury. For recording, the whole sacrocaudal spinal cord was removed and maintained in vitro in normal artificial cerebral spinal fluid (nACSF), without application of neuromodulators. During a slow triangular voltage-clamp command (ramp) a PIC was activated with a threshold of –54.2 ± 4.8 mV (similar to plateau threshold), with a peak current of 2.88 ± 0.95 nA and produced a pronounced negative-slope region in the V–I relation. This PIC was in part mediated by Cav1.3 L-type calcium channels because it was low threshold and significantly reduced by 10 to 20 μM nimodipine or 400 μM Cd2+. The PIC that remained during a calcium channel blockade (in Cd2+) was completely and rapidly blocked by tetrodotoxin (TTX; 0.5 to 2 μM), and thus was a TTX-sensitive persistent sodium current. This persistent sodium current was activated rapidly about 7 mV below the spike threshold (spike threshold –46.1 ± 4.5 mV), contributed approximately 1/2 of the initial peak of the total PIC, inactivated partly to contribute only approximately 1/3 of the sustained PIC (at 5 to 10 s), and deactivated rapidly with hyperpolarization (<50 ms). When TTX was added to the bath first, the nimodipine-sensitive persistent calcium current (L-type) was seen in isolation; it was slowly activated (>250 ms), had a low but variable threshold (either slightly above or below the spike threshold), contributed the other approximately 1/2 of the initial peak of the total PIC (before TTX), did not usually inactivate with time (contributed approximately two-thirds of the sustained PIC), and deactivated slowly with hyperpolarization to rest (in >300 ms). In summary, low-threshold persistent calcium (Cav1.3) and sodium currents spontaneously develop in motoneurons of chronic spinal rats and these enable large, rapidly activated plateaus that ultimately lead to spasticity.

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 Persistent Sodium Current Contributes to Induced Voltage Oscillations in Locomotor-Related Hb9 Interneurons in the Mouse Spinal Cord

2008 ◽  
Vol 100 (4) ◽  
pp. 2254-2264 ◽  
Author(s):  
Lea Ziskind-Conhaim ◽  
Linying Wu ◽  
Eric P. Wiesner
Keyword(s):  
Spinal Cord ◽  
Synaptic Transmission ◽  
Sodium Current ◽  
Rhythmic Activity ◽  
Inhibitory Synapses ◽  
Persistent Sodium Current ◽  
Induced Membrane ◽  
Mouse Spinal Cord ◽  
Rhythmic Motor ◽  
Membrane Oscillations

Neurochemically induced membrane voltage oscillations and firing episodes in spinal excitatory interneurons expressing the HB9 protein (Hb9 INs) are synchronous with locomotor-like rhythmic motor outputs, suggesting that they contribute to the excitatory drive of motoneurons during locomotion. Similar to central pattern generator neurons in other systems, Hb9 INs are interconnected via electrical coupling, and their rhythmic activity does not depend on fast glutamatergic synaptic transmission. The primary objective of this study was to determine the contribution of fast excitatory and inhibitory synaptic transmission and subthreshold voltage-dependent currents to the induced membrane oscillations in Hb9 INs in the postnatal mouse spinal cord. The non- N-methyl-d-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reduced the amplitude of voltage oscillations but did not alter their frequency. CNQX suppressed rhythmic motor activity. Blocking glycine and GABAA receptor-mediated inhibitory synapses as well as cholinergic transmission did not change the properties of CNQX-resistant membrane oscillations. However, disinhibition triggered new episodes of slow motor bursting that were not correlated with induced locomotor-like rhythms in Hb9 INs. Our observations indicated that fast excitatory and inhibitory synaptic inputs did not control the frequency of induced rhythmic activity in Hb9 INs. We next examined the contribution of persistent sodium current ( INaP) to subthreshold membrane oscillations in the absence of primary glutamatergic, GABAergic and glycinergic synaptic drive to Hb9 INs. Low concentrations of riluzole that blocked the slow-inactivating component of sodium current gradually suppressed the amplitude and reduced the frequency of voltage oscillations. Our finding that INaP regulates locomotor-related rhythmic activity in Hb9 INs independently of primary synaptic transmission supports the concept that these neurons constitute an integral component of the rhythmogenic locomotor network in the mouse spinal cord.

scholarly journals A Negative Slope Conductance of the Persistent Sodium Current Prolongs Subthreshold Depolarizations

2017 ◽  
Vol 113 (10) ◽  
pp. 2207-2217 ◽  
Author(s):  
Cesar C. Ceballos ◽  
Antonio C. Roque ◽  
Ricardo M. Leão
Keyword(s):  
Sodium Current ◽  
Negative Slope ◽  
Persistent Sodium Current

Contribution of Persistent Sodium Current to Locomotor Pattern Generation in Neonatal Rats

2007 ◽  
Vol 98 (2) ◽  
pp. 613-628 ◽  
Author(s):  
Sabrina Tazerart ◽  
Jean-Charles Viemari ◽  
Pascal Darbon ◽  
Laurent Vinay ◽  
Frédéric Brocard
Keyword(s):  
Spinal Cord ◽  
Sodium Current ◽  
Input Resistance ◽  
Firing Frequency ◽  
Pattern Generation ◽  
Neonatal Rat ◽  
Persistent Sodium Current ◽  
Locomotor Pattern ◽  
Functional Features

The persistent sodium current ( INaP) is known to play a role in rhythm generation in different systems. Here, we investigated its contribution to locomotor pattern generation in the neonatal rat spinal cord. The locomotor network is mainly located in the ventromedial gray matter of upper lumbar segments. By means of whole cell recordings in slices, we characterized membrane and INaP biophysical properties of interneurons located in this area. Compared with motoneurons, interneurons were more excitable, because of higher input resistance and membrane time constant, and displayed lower firing frequency arising from broader spikes and longer AHPs. Ramp voltage-clamp protocols revealed a riluzole- or TTX-sensitive inward current, presumably INaP, three times smaller in interneurons than in motoneurons. However, in contrast to motoneurons, INaP mediated a prolonged plateau potential in interneurons after reducing K+ and Ca2+ currents. We further used in vitro isolated spinal cord preparations to investigate the contribution of INaP to locomotor pattern. Application of riluzole (10 μM) to the whole spinal cord or to the upper lumbar segments disturbed fictive locomotion, whereas application of riluzole over the caudal lumbar segments had no effect. The effects of riluzole appeared to arise from a specific blockade of INaP because action potential waveform, dorsal root–evoked potentials, and miniature excitatory postsynaptic currents were not affected. This study provides new functional features of ventromedial interneurons, with the first description of INaP-mediated plateau potentials, and new insights into the operation of the locomotor network with a critical implication of INaP in stabilizing the locomotor pattern.

Evidence for Plateau Potentials in Tail Motoneurons of Awake Chronic Spinal Rats With Spasticity

2001 ◽  
Vol 86 (4) ◽  
pp. 1972-1982 ◽  
Author(s):  
David J. Bennett ◽  
Yunru Li ◽  
Philip J. Harvey ◽  
Monica Gorassini
Keyword(s):  
Spinal Cord ◽  
Firing Rate ◽  
Motor Unit ◽  
Synaptic Input ◽  
Control Unit ◽  
Motor Units ◽  
Test Unit ◽  
Plateau Potentials ◽  
Motor Unit Firing ◽  
Chronic Spinal Rats

Motor units of segmental tail muscles were recorded in awake rats following acute (1–2 days) and chronic (>30 days) sacral spinal cord transection to determine whether plateau potentials contributed to sustained motor-unit discharges after injury. This study was motivated by a companion in vitro study that indicated that after chronic spinal cord injury, the tail motoneurons of the sacrocaudal spinal cord exhibit persistent inward currents ( I PIC) that cause intrinsically sustained depolarizations ( plateau potentials) and firing ( self-sustained firing). Importantly, in this companion study, the plateaus were fully activated at recruitment and subsequently helped sustain the firing without causing abrupt nonlinearities in firing. That is, after recruitment and plateau activation, the firing rate was modulated relatively linearly with injected current and therefore provided a good approximation of the input to the motoneuron despite the plateau. Thus in the present study, pairs of motor units were recorded simultaneously from the same muscle, and the firing rate ( F) of the lowest-threshold unit (control unit) was used as an estimate of the synaptic input to both units. We then examined whether firing of the higher-threshold unit (test unit) was intrinsically maintained by a plateau, by determining whether more synaptic input was required to recruit the test unit than to maintain its firing. The difference in the estimated synaptic input at recruitment and de-recruitment of the test unit (i.e., change in control unit rate, Δ F) was taken as an estimate of the plateau current ( I PIC) that intrinsically sustained the firing. Slowly graded manual skin stimulation was used to recruit and then de-recruit the units. The test unit was recruited when the control unit rate was on average 17.8 and 18.9 Hz in acute and chronic spinal rats, respectively. In chronic spinal rats, the test unit was de-recruited when the control unit rate (re: estimated synaptic input) was significantly reduced, compared with at recruitment (Δ F = −5.5 Hz), and thus a plateau participated in maintaining the firing. In the lowest-threshold motor units, even a brief stimulation triggered very long-lasting firing (seconds to hours; self-sustained firing). Higher-threshold units required continuous stimulation (or a spontaneous spasm) to cause firing, but again more synaptic input was needed to recruit the unit than to maintain its firing (i.e., plateau present). In contrast, in acute spinal rats, the stimulation did not usually trigger sustained motor-unit firing that could be attributed to plateaus because Δ F was not significantly different from zero. These results indicate that plateaus play an important role in sustaining motor-unit firing in awake chronic spinal rats and thus contribute to the hyperreflexia and hypertonus associated with chronic injury.

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.

Muscarinic Enhancement of Persistent Sodium Current Synchronizes Striatal Medium Spiny Neurons

2009 ◽  
Vol 102 (2) ◽  
pp. 682-690 ◽  
Author(s):  
Luis Carrillo-Reid ◽  
Fatuel Tecuapetla ◽  
Nicolas Vautrelle ◽  
Adán Hernández ◽  
Ramiro Vergara ◽  
...  
Keyword(s):  
Sodium Current ◽  
Network Dynamics ◽  
Receptor Activation ◽  
Procedural Memory ◽  
Negative Slope ◽  
Medium Spiny Neurons ◽  
Persistent Sodium Current ◽  
Intrinsic Properties ◽  
Bistable Behavior ◽  
Spiny Neurons

Network dynamics denoted by synchronous firing of neuronal pools rely on synaptic interactions and intrinsic properties. In striatal medium spiny neurons, N-methyl-d-aspartate (NMDA) receptor activation endows neurons with nonlinear capabilities by inducing a negative-slope conductance region (NSCR) in the current–voltage relationship. Nonlinearities underlie associative learning, procedural memory, and the sequential organization of behavior in basal ganglia nuclei. The cholinergic system modulates the function of medium spiny projection neurons through the activation of muscarinic receptors, increasing the NMDA-induced NSCR. This enhancement is reflected as a change in the NMDA-induced network dynamics, making it more synchronous. Nevertheless, little is known about the contribution of intrinsic properties that promote this activity. To investigate the mechanisms underlying the cholinergic modulation of bistable behavior in the striatum, we used whole cell and calcium-imaging techniques. A persistent sodium current modulated by muscarinic receptor activation participated in the enhancement of the NSCR and the increased network synchrony. These experiments provide evidence that persistent sodium current generates bistable behavior in striatal neurons and contributes to the regulation of synchronous network activity. The neuromodulation of bistable properties could represent a cellular and network mechanism for cholinergic actions in the striatum.

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.

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