Computational Estimation of the Distribution of L-type Ca2+Channels in Motoneurons Based on Variable Threshold of Activation of Persistent Inward Currents

2006 ◽  
Vol 95 (1) ◽  
pp. 225-241 ◽  
Author(s):  
Tuan V. Bui ◽  
Maria Ter-Mikaelian ◽  
Diane Bedrossian ◽  
P. Ken Rose
Keyword(s):  
Persistent Inward Currents ◽  
Variable Threshold ◽  
Computational Estimation ◽  
Inward Currents ◽  
Ca2 Channels

scholarly journals Estimates of the Location of L-type Ca2+ Channels in Motoneurons of Different Sizes: A Computational Study

2007 ◽  
Vol 97 (6) ◽  
pp. 4023-4035 ◽  
Author(s):  
Giovanbattista Grande ◽  
Tuan V. Bui ◽  
P. Ken Rose
Keyword(s):  
Computational Study ◽  
Dendritic Tree ◽  
Synaptic Activity ◽  
Dendritic Trees ◽  
Persistent Inward Currents ◽  
Size Dependent ◽  
Dendritic Location ◽  
Inward Currents ◽  
The Relationship ◽  
Ca2 Channels

In the presence of monoamines, L-type Ca2+ channels on the dendrites of motoneurons contribute to persistent inward currents (PICs) that can amplify synaptic inputs two- to sixfold. However, the exact location of the L-type Ca2+ channels is controversial, and the importance of the location as a means of regulating the input-output properties of motoneurons is unknown. In this study, we used a computational strategy developed previously to estimate the dendritic location of the L-type Ca2+ channels and test the hypothesis that the location of L-type Ca2+ channels varies as a function of motoneuron size. Compartmental models were constructed based on dendritic trees of five motoneurons that ranged in size from small to large. These models were constrained by known differences in PIC activation reported for low- and high-conductance motoneurons and the relationship between somatic PIC threshold and the presence or absence of tonic excitatory or inhibitory synaptic activity. Our simulations suggest that L-type Ca2+ channels are concentrated in hotspots whose distance from the soma increases with the size of the dendritic tree. Moving the hotspots away from these sites (e.g., using the hotspot locations from large motoneurons on intermediate-sized motoneurons) fails to replicate the shifts in PIC threshold that occur experimentally during tonic excitatory or inhibitory synaptic activity. In models equipped with a size-dependent distribution of L-type Ca2+ channels, the amplification of synaptic current by PICs depends on motoneuron size and the location of the synaptic input on the dendritic tree.

Hyperexcitability at sites of nerve injury depends on voltage-sensitive Na+ channels

1994 ◽  
Vol 72 (1) ◽  
pp. 349-359 ◽  
Author(s):  
O. Matzner ◽  
M. Devor
Keyword(s):  
Nerve Injury ◽  
Duty Cycle ◽  
Firing Frequency ◽  
Na Channel ◽  
Channel Blockers ◽  
Na Channels ◽  
Experimental Conditions ◽  
K Channels ◽  
Inward Currents ◽  
Ca2 Channels

1. We used the tested fiber method to record from single myelinated afferents axons ending in a chronic nerve injury site (neuroma) in the rat sciatic nerve or L4,5 dorsal root. Axons were chosen for study that fired spontaneously with a stable tonic or interrupted (bursty) autorhythmic firing pattern. 2. Agents that block voltage-sensitive Na+ channels [tetrodotoxin (TTX), lidocaine], voltage-sensitive Ca2+ channels (Cd2+, Co2+, Ni2+, verapamil, D600, nifedipine, and fluarizine), volt-age-sensitive K+ channels [tetraethylammonium (TEA), 4-aminopyridine (4-AP)], and Ca(2+)-activated K+ channels (gK+Ca2+;quinidine, apamine) were applied topically to the neuroma. Effects on baseline rhythmogenesis and on the duty cycle of bursting were documented. Spike pattern analysis was used to determine whether changes in firing frequency were associated with changes in impulse initiation (electrogenesis), or resulted from (partial) block of impulse propagation downstream from the site of electrogenesis. Effects of veratridine were also noted. 3. Na+ channel blockers consistently quenched neuroma firing, and they did so by suppressing the process of impulse initiation. Only rarely was propagation block the dominant process. In bursty fibers the duration of on-periods shortened as the duration of off-periods lengthened, without a significant change in the baseline interspike interval (ISI). Veratridine accelerated firing, also via the impulse generating process. 4. Ca2+ channel blockers had essentially no effect on baseline firing rate (i.e., ISI). 5. Ca2+ channel blockers, as well as blockers of gK+Ca2+, had substantial, but inconsistent effects on burst pattern. It is not clear whether this reflects variability in the experimental conditions, or heterogeneity among the fibers sampled. 6. Blockade of K+ channels failed to evoke rhythmogenesis in acutely cut axons as it does in chronically injured axons, even in the presence of veratridine. This is consistent with other evidence that ectopic neuroma firing depends on postinjury remodeling of membrane electrical properties. 7. The data indicate that, in chronically injured axons, the inward currents that underly electrogenicity, enable ectopic discharge, and, together with outward K+ currents, set the fundamental firing rhythm (ISI), operate primarily with the use of voltage-sensitive Na+ rather than Ca2+ channels. 8. The on-off duty cycle in bursty fibers was affected by Na+ channel ligands and also, although less so, and less consistently by, Ca2+ channel ligands. This indicates that both may play a role in the slow modulations of membrane potential that presumably underly interrupted autorhythmicity.

scholarly journals Evidence for Increased Activation of Persistent Inward Currents in Individuals With Chronic Hemiparetic Stroke

2008 ◽  
Vol 100 (6) ◽  
pp. 3236-3243 ◽  
Author(s):  
Jacob G. McPherson ◽  
Michael D. Ellis ◽  
C. J. Heckman ◽  
Julius P. A. Dewald
Keyword(s):  
Repeated Measures ◽  
Afferent Feedback ◽  
Joint Torque ◽  
Emg Activity ◽  
Tonic Vibration Reflex ◽  
Stretch Reflexes ◽  
Persistent Inward Currents ◽  
Inward Currents ◽  
Hemiparetic Stroke ◽  
Chronic Hemiparetic Stroke

Despite the prevalence of hyperactive stretch reflexes in the paretic limbs of individuals with chronic hemiparetic stroke, the fundamental pathophysiological mechanisms responsible for their expression remain poorly understood. This study tests whether the manifestation of hyperactive stretch reflexes following stroke is related to the development of persistent inward currents (PICs) leading to hyperexcitability of motoneurons innervating the paretic limbs. Because repetitive volleys of 1a afferent feedback can elicit PICs, this investigation assessed motoneuronal excitability by evoking the tonic vibration reflex (TVR) of the biceps muscle in 10 awake individuals with chronic hemiparetic stroke and measuring the joint torque and electromyographic (EMG) responses of the upper limbs. Elbow joint torque and the EMG activity of biceps, brachioradialis, and the long and lateral heads of triceps brachii were recorded during 8 s of 112-Hz biceps vibration (evoking the TVR) and for 5 s after cessation of stimulation. Repeated-measures ANOVA tests revealed significantly ( P ≤ 0.05) greater increases in elbow flexion torque and EMG activity in the paretic as compared with the nonparetic limbs, both during and up to 5 s following biceps vibration. The finding of these augmentations exclusively in the paretic limb suggests that contralesional motoneurons may become hyperexcitable and readily invoke PICs following stroke. An enhanced tendency to evoke PICs may be due to an increased subthreshold depolarization of motoneurons, an increased monoaminergic input from the brain stem, or both.

scholarly journals Effects of Baclofen on Spinal Reflexes and Persistent Inward Currents in Motoneurons of Chronic Spinal Rats With Spasticity

2004 ◽  
Vol 92 (5) ◽  
pp. 2694-2703 ◽  
Author(s):  
Y. Li ◽  
X. Li ◽  
P. J. Harvey ◽  
D. J. Bennett
Keyword(s):  
Spinal Cord ◽  
Ventral Root ◽  
Spinal Reflexes ◽  
Monosynaptic Reflex ◽  
Persistent Inward Currents ◽  
Inward Currents ◽  
Muscle Spasms ◽  
Acute Spinal Rats ◽  
Chronic Spinal Rats ◽  
Higher Doses

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.

Sequential activation of multiple persistent inward currents induces staircase currents in serotonergic neurons of medulla in ePet-EYFP mice

2020 ◽  
Vol 123 (1) ◽  
pp. 277-288
Author(s):  
Yi Cheng ◽  
Qiang Zhang ◽  
Yue Dai
Keyword(s):  
High Voltage ◽  
Low Voltage ◽  
Spinal Neurons ◽  
Serotonergic Neurons ◽  
Persistent Inward Currents ◽  
Functional Roles ◽  
Bath Application ◽  
Voltage Ramp ◽  
Inward Currents ◽  
Sequential Activation

Persistent inward currents (PICs) are widely reported in rodent spinal neurons. A distinctive pattern observed recently is staircase-like PICs induced by voltage ramp in serotonergic neurons of mouse medulla. The mechanism underlying this pattern of PICs is unclear. Combining electrophysiological, pharmacological, and computational approaches, we investigated the staircase PICs in serotonergic neurons of medulla in ePet-EYFP transgenic mice (postnatal days 1–7). Staircase PICs induced by 10-s voltage biramps were observed in 70% of serotonergic neurons ( n = 73). Staircase PICs activated at −48.8 ± 5 mV and consisted of two components, with the first PIC of 45.8 ± 51 pA and the second PIC of 197.3 ± 126 pA ( n = 51). Staircase PICs were also composed of low-voltage-activated sodium PIC (Na-PIC; onset −46.2 ± 5 mV, n = 34), high-voltage-activated calcium PIC (Ca-PIC; onset −29.3 ± 6 mV, n = 23), and high-voltage-activated tetrodotoxin (TTX)- and dihydropyridine-resistant sodium PIC (TDR-PIC; onset −16.8 ± 4 mV, n = 28). Serotonergic neurons expressing Na-PIC, Ca-PIC, and TDR-PIC were evenly distributed in medulla. Bath application of 1–2 μM TTX blocked the first PIC and decreased the second PIC by 36% ( n = 23, P < 0.05). Nimodipine (25 μM) reduced the second PIC by 38% ( n = 34, P < 0.001) without altering the first PIC. TTX and nimodipine removed the first PIC and reduced the second PIC by 59% ( n = 28, P < 0.01). A modeling study mimicked the staircase PICs and verified experimental conclusions that sequential activation of Na-PIC, Ca-PIC, and TDR-PIC in order of voltage thresholds induced staircase PICs in serotonergic neurons. Further experimental results suggested that the multiple components of staircase PICs play functional roles in regulating excitability of serotonergic neurons in medulla. NEW & NOTEWORTHY Staircase persistent inward currents (PICs) are mediated by activation of L-type calcium channels in dendrites of mouse spinal motoneurons. A novel mechanism is explored in this study. Here we report that the staircase PICs are mediated by sequentially activating sodium and calcium PICs in serotonergic neurons of mouse medulla.

scholarly journals PICs in motoneurons do not scale with the size of the animal: a possible mechanism for faster speed of muscle contraction in smaller species

2017 ◽  
Vol 118 (1) ◽  
pp. 93-102 ◽  
Author(s):  
Seoan Huh ◽  
Ramamurthy Siripuram ◽  
Robert H. Lee ◽  
Vladimir V. Turkin ◽  
Derek O’Neill ◽  
...  
Keyword(s):  
Electrical Properties ◽  
Muscle Fibers ◽  
Small Animal ◽  
Spinal Motoneurons ◽  
Persistent Inward Currents ◽  
Firing Rates ◽  
Adult Mice ◽  
Inward Currents ◽  
Animal Size

The majority of studies on the electrical properties of neurons are carried out in rodents, and in particular in mice. However, the minute size of this animal compared with humans potentially limits the relevance of the resulting insights. To be able to extrapolate results obtained in a small animal such as a rodent, one needs to have proper knowledge of the rules governing how electrical properties of neurons scale with the size of the animal. Generally speaking, electrical resistances of neurons increase as cell size decreases, and thus maintenance of equal depolarization across cells of different sizes requires the underlying currents to decrease in proportion to the size decrease. Thus it would generally be expected that voltage-sensitive currents are smaller in smaller animals. In this study, we used in vivo preparations to record electrical properties of spinal motoneurons in deeply anesthetized adult mice and cats. We found that PICs do not scale with size, but instead are constant in their amplitudes across these species. This constancy, coupled with the threefold differences in electrical resistances, means that PICs contribute a threefold larger depolarization in the mouse than in the cat. As a consequence, motoneuronal firing rate sharply increases as animal size decreases. These differences in firing rates are likely essential in allowing different species to control muscles with widely different contraction speeds (smaller animals have faster muscle fibers). Thus from our results we have identified a possible new mechanism for how electrical properties are tuned to match mechanical properties within the motor output system. NEW & NOTEWORTHY The small size of the mouse warrants concern over whether the properties of their neurons are a scaled version of those in larger animals or instead have unique features. Comparison of spinal motoneurons in mice to cats showed unique features. Firing rates in the mouse were much higher, in large part due to relatively larger persistent inward currents. These differences likely reflect adaptations for controlling much faster muscle fibers in mouse than cat.

scholarly journals Nonlinear Input-Output Functions of Motoneurons

Physiology ◽  
2020 ◽  
Vol 35 (1) ◽  
pp. 31-39 ◽  
Author(s):  
Marc D. Binder ◽  
Randall K. Powers ◽  
C. J. Heckman
Keyword(s):  
Motor Control ◽  
Nonlinear Behavior ◽  
Comprehensive Model ◽  
Input Output ◽  
Persistent Inward Currents ◽  
Voltage Gated ◽  
Motor Commands ◽  
Nonlinear Input ◽  
Inward Currents

All movements are generated by the activation of motoneurons, and hence their input-output properties define the final step in processing of all motor commands. A major challenge to understanding this transformation has been the striking nonlinear behavior of motoneurons conferred by the activation of persistent inward currents (PICs) mediated by their voltage-gated Na+ and Ca2+ channels. In this review, we focus on the contribution that these PICs make to motoneuronal discharge and how the nonlinearities they engender impede the construction of a comprehensive model of motor control.

Ca(2+)-induced inhibition of 45Ca2+ influx and Ca2+ current in smooth muscle of the rat vas deferens

1996 ◽  
Vol 270 (5) ◽  
pp. C1468-C1477 ◽  
Author(s):  
M. A. Khoyi ◽  
T. Ishikawa ◽  
K. D. Keef ◽  
D. P. Westfall
Keyword(s):  
Vas Deferens ◽  
Rat Vas Deferens ◽  
Inhibitory Effects ◽  
Isolated Cells ◽  
Inositol 1,4,5 Trisphosphate ◽  
Voltage Dependent ◽  
Steady State Inactivation ◽  
Inward Currents ◽  
K Concentration ◽  
Ca2 Channels

The present study investigates how changes in intracellular Ca2+ concentration modulate the influx of 45Ca2+ in isolated rat vasa deferentia. Raising extracellular K+ concentration ([K+]0) to > or = 32 mM increased 45Ca2+ influx during the 1st min in solutions containing 0.03-1.5 mM extracellular Ca2+ concentration ([Ca2+]0). During the 6th min in [K+]0 > or = 50 mM, 45Ca2+ influx was less than during the 1st min. This decline in 45Ca2+ influx occurred for [Ca2+]0 > or = 0.4 mM. Procaine potentiated K(+)-stimulated 45Ca2+ influx in 1.5 mM [Ca2+]0 and eliminated the decline of 45Ca2+ influx in low [Ca2-]0. Ryanodine and norepinephrine reduced K(+)-stimulated 45Ca2+ influx. 45Ca2+ content changed with time in accordance with the changes observed in 45Ca2+ influx. In isolated cells, voltage-dependent inward currents inactivated more rapidly with 1.5 mM Ca2+ as the charge carrier than with 1.5 mM Ba2+, and the steady-state inactivation relationship was shifted in the hyperpolarizing direction. Inward current was reduced with either caffeine, ryanodine, or norepinephrine. The inhibitory effects of norepinephrine were abolished by depletion of intracellular Ca2+ stores. These results are compatible with the hypothesis that K(+)-stimulated 45Ca2+ influx declines with time due to Ca(2+)-induced inhibition of Ca2- channels. Ca(2+)- and inositol 1,4,5-trisphosphate-induced releases of Ca2+ from the sarcoplasmic reticulum appear to play an important role in this process.

scholarly journals Estimation of the Contribution of Intrinsic Currents to Motoneuron Firing Based on Paired Motoneuron Discharge Records in the Decerebrate Cat

2008 ◽  
Vol 100 (1) ◽  
pp. 292-303 ◽  
Author(s):  
Randall K. Powers ◽  
Paul Nardelli ◽  
T. C. Cope
Keyword(s):  
Firing Rate ◽  
Motor Units ◽  
Unit Discharge ◽  
Decerebrate Cat ◽  
Persistent Inward Currents ◽  
Quantitative Estimates ◽  
Number Of Factors ◽  
Inward Currents ◽  
The Difference ◽  
Synaptic Drive

Motoneuron activation is strongly influenced by persistent inward currents (PICs) flowing through voltage-sensitive channels. PIC characteristics and their contribution to the control of motoneuron firing rate have been extensively described in reduced animal preparations, but their contribution to rate modulation in human motoneurons is controversial. It has recently been proposed that the analysis of discharge records of a simultaneously recorded pair of motor units can be used to make quantitative estimates of the PIC contribution, based on the assumption that the firing rate of an early recruited (reporter) unit can be used as a measure of the synaptic drive to a later recruited (test) unit. If the test unit's discharge is augmented by PICs, less synaptic drive will be required to sustain discharge than required to initially recruit it, and the difference in reporter unit discharge (Δ F) at test recruitment and de-recruitment is a measure of the size of the PIC contribution. We applied this analysis to discharge records of pairs of motoneurons in the decerebrate cat preparation, in which motoneuron PICs have been well-characterized and are known to be prominent. Mean Δ F values were positive in 58/63 pairs, and were significantly greater than zero in 40/63 pairs, as would be expected based on PIC characteristics recorded in this preparation. However, several lines of evidence suggest that the Δ F value obtained in a particular motoneuron pair may depend on a number of factors other than the PIC contribution to firing rate.

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