scholarly journals Maturation of persistent and hyperpolarization-activated inward currents shape the recruitment of motoneuron subtypes during postnatal development

2021 ◽  
Author(s):  
Simon A Sharples ◽  
Gareth B Miles
Keyword(s):  
Postnatal Development ◽  
Motor Units ◽  
Fine Motor ◽  
Muscle Fibres ◽  
Intrinsic Properties ◽  
Size Principle ◽  
Complex Behaviour ◽  
Whole Cell Patch Clamp ◽  
Inward Currents ◽  
Fine Control

The fine control of movement is a prerequisite for complex behaviour and is mediated by the orderly recruitment of motor units composed of slow and fast twitch muscle fibres. The size principle was initially proposed to account for orderly recruitment; however, motoneuron size is a poor predictor of recruitment amongst functionally defined motor unit subtypes. While intrinsic properties of motoneurons are key regulators of motoneuron recruitment, the underlying currents involved are not well defined. Whole-cell patch-clamp electrophysiology was deployed to study intrinsic properties, and the underlying currents, that contribute to the differential recruitment of fast and slow motoneurons. Motoneurons were studied during the first three postnatal weeks in mice to identify key properties that establish orderly recruitment and contribute to the emergence of fine motor control. We find that fast and slow motoneurons are functionally homogeneous during the first postnatal week and are recruited based on size, irrespective of motoneuron subtype. The recruitment of fast and slow motoneurons becomes staggered during the second postnatal week due to the differential maturation of passive and active properties, particularly persistent inward currents (PICs). The current required to recruit fast motoneurons increases further in the third postnatal week, despite no additional changes in passive properties or PICs. This further staggering of recruitment currents reflects development of a hyperpolarization-activated inward current during week 3. Our results suggest that motoneuron recruitment is multifactorial, with recruitment order established during postnatal development through the differential maturation of passive properties and sequential integration of persistent and hyperpolarization-activated inward currents.

scholarly journals Maturation of persistent and hyperpolarization-activated inward currents shapes the differential activation of motoneuron subtypes during postnatal development

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Simon A Sharples ◽  
Gareth B Miles
Keyword(s):  
Postnatal Development ◽  
Motor Units ◽  
Intrinsic Properties ◽  
Size Principle ◽  
Differential Activation ◽  
Persistent Inward Currents ◽  
Poor Predictor ◽  
Whole Cell Patch Clamp ◽  
Inward Currents ◽  
Patch Clamp Electrophysiology

The size principle underlies the orderly recruitment of motor units; however, motoneuron size is a poor predictor of recruitment amongst functionally defined motoneuron subtypes. Whilst intrinsic properties are key regulators of motoneuron recruitment, the underlying currents involved are not well defined. Whole-cell patch-clamp electrophysiology was deployed to study intrinsic properties, and the underlying currents, that contribute to the differential activation of delayed and immediate firing motoneuron subtypes. Motoneurons were studied during the first three postnatal weeks in mice to identify key properties that contribute to rheobase and may be important to establish orderly recruitment. We find that delayed and immediate firing motoneurons are functionally homogeneous during the first postnatal week and are activated based on size, irrespective of subtype. The rheobase of motoneuron subtypes become staggered during the second postnatal week, which coincides with the differential maturation of passive and active properties, particularly persistent inward currents. Rheobase of delayed firing motoneurons increases further in the third postnatal week due to the development of a prominent resting hyperpolarization-activated inward current. Our results suggest that motoneuron recruitment is multifactorial, with recruitment order established during postnatal development through the differential maturation of passive properties and sequential integration of persistent and hyperpolarization-activated inward currents.

scholarly journals Metabolic cost underlies task-dependent variations in motor unit recruitment

2018 ◽  
Vol 15 (148) ◽  
pp. 20180541 ◽  
Author(s):  
Adrian K. M. Lai ◽  
Andrew A. Biewener ◽  
James M. Wakeling
Keyword(s):  
Cost Function ◽  
Motor Unit ◽  
Metabolic Cost ◽  
Motor Units ◽  
Recruitment Strategy ◽  
Muscle Fibre Types ◽  
Muscle Fibres ◽  
Recruitment Strategies ◽  
Size Principle ◽  
Low Intensity

Mammalian skeletal muscles are comprised of many motor units, each containing a group of muscle fibres that have common contractile properties: these can be broadly categorized as slow and fast twitch muscle fibres. Motor units are typically recruited in an orderly fashion following the ‘size principle’, in which slower motor units would be recruited for low intensity contraction; a metabolically cheap and fatigue-resistant strategy. However, this recruitment strategy poses a mechanical paradox for fast, low intensity contractions, in which the recruitment of slower fibres, as predicted by the size principle, would be metabolically more costly than the recruitment of faster fibres that are more efficient at higher contraction speeds. Hence, it would be mechanically and metabolically more effective for recruitment strategies to vary in response to contraction speed so that the intrinsic efficiencies and contraction speeds of the recruited muscle fibres are matched to the mechanical demands of the task. In this study, we evaluated the effectiveness of a novel, mixed cost function within a musculoskeletal simulation, which includes the metabolic cost of contraction, to predict the recruitment of different muscle fibre types across a range of loads and speeds. Our results show that a metabolically informed cost function predicts favoured recruitment of slower muscle fibres for slower and isometric tasks versus recruitment that favours faster muscles fibres for higher velocity contractions. This cost function predicts a change in recruitment patterns consistent with experimental observations, and also predicts a less expensive metabolic cost for these muscle contractions regardless of speed of the movement. Hence, our findings support the premise that varying motor recruitment strategies to match the mechanical demands of a movement task results in a mechanically and metabolically sensible way to deploy the different types of motor unit.

scholarly journals Effects of persistent inward currents, accommodation, and adaptation on motor unit behavior: a simulation study

2011 ◽  
Vol 106 (3) ◽  
pp. 1467-1479 ◽  
Author(s):  
Ann L. Revill ◽  
Andrew J. Fuglevand
Keyword(s):  
Motor Neurons ◽  
Synaptic Input ◽  
Human Subjects ◽  
Motor Units ◽  
Intrinsic Properties ◽  
Persistent Inward Currents ◽  
Nonlinear Properties ◽  
Contraction Duration ◽  
Inward Currents ◽  
The Difference

Motor neurons are often assumed to generate spikes in proportion to the excitatory synaptic input received. There are, however, many intrinsic properties of motor neurons that might affect this relationship, such as persistent inward currents (PICs), spike-threshold accommodation, or spike-frequency adaptation. These nonlinear properties have been investigated in reduced animal preparation but have not been well studied during natural motor behaviors because of the difficulty in characterizing synaptic input in intact animals. Therefore, we studied the influence of each of these intrinsic properties on spiking responses and muscle force using a population model of motor units that simulates voluntary contractions in human subjects. In particular, we focused on the difference in firing rate of low-threshold motor units when higher threshold motor units were recruited and subsequently derecruited, referred to as ΔF. Others have used ΔF to evaluate the extent of PIC activation during voluntary behavior. Our results showed that positive ΔF values could arise when any one of these nonlinear properties was included in the simulations. Therefore, a positive ΔF should not be considered as exclusive evidence for PIC activation. Furthermore, by systematically varying contraction duration and speed in our simulations, we identified a means that might be used experimentally to distinguish among PICs, accommodation, and adaptation as contributors to ΔF.

Functional Properties of Single Motor Units in the Inferior Head of Human Lateral Pterygoid Muscle: Task Firing Rates

2002 ◽  
Vol 88 (2) ◽  
pp. 751-760 ◽  
Author(s):  
I. Phanachet ◽  
T. Whittle ◽  
K. Wanigaratne ◽  
G. M. Murray
Keyword(s):  
Firing Rate ◽  
Correlation Coefficients ◽  
Motor Units ◽  
Lateral Pterygoid Muscle ◽  
Jaw Movements ◽  
Firing Rates ◽  
Single Motor ◽  
Single Motor Units ◽  
Fine Control ◽  
Contralateral Movement

The precise function of the inferior head of the human lateral pterygoid muscle (IHLP) is unclear. The aim of this study was to clarify the normal function of the IHLP. The hypothesis was that an important function of the IHLP is the generation and fine control of horizontal (i.e., anteroposterior and mediolateral) jaw movements. The activities of 50 single motor units (SMUs) were recorded from IHLP (14 subjects) during two- or three-step contralateral movement ( n = 36) and/or protrusion ( n = 33). Most recording sites were identified by computer tomography. There was a statistically significant overall increase in firing rate as the magnitude of jaw displacement increased between the holding phases (range of increments: 0.3–1.6 mm). The firing rates during the dynamic phases for each unit were significantly greater than those during the previous holding phases but less than those during the subsequent holding phases. For the contralateral step task at the intermediate rate, the cross-correlation coefficients between jaw displacement in the mediolateral axis and the mean firing rate of each unit ranged from r = 0.29 to 0.77; mean ± SD; r = 0.49 ± 0.13 (protrusive step task: r = 0.12–0.74, r = 0.44 ± 0.14 for correlation with anterior–posterior axis). The correlation coefficients at the fast rate during the contralateral step task and the protrusive step task were significantly higher than those at the slow rate. The firing rate change of the SMUs per unit displacement between holding phases was significantly greater for the lower-threshold than for the higher-threshold units during contralateral movement and protrusion. After dividing IHLP into four regions, the SMUs recorded in the superior part exhibited significantly greater mean firing rate changes per unit displacement during protrusion than for the SMUs recorded in the inferior part. Significantly fewer units were related to the protrusive task in the superior–medial part. These data support previously proposed notions of functional heterogeneity within IHLP. The present findings provide further evidence for an involvement of the IHLP in the generation and fine control of horizontal jaw movements.

Inhibition of inwardly rectifying K+ channels by cGMP in pulmonary vascular endothelial cells

2002 ◽  
Vol 283 (2) ◽  
pp. L297-L304 ◽  
Author(s):  
Larissa A. Shimoda ◽  
Laura E. Welsh ◽  
David B. Pearse
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Vascular Endothelial Cells ◽  
Cell Types ◽  
Protective Mechanism ◽  
Cell Integrity ◽  
Barrier Dysfunction ◽  
Whole Cell Patch Clamp ◽  
Inward Currents ◽  
Inwardly Rectifying

Endothelial barrier dysfunction is typically triggered by increased intracellular Ca2+concentration. Membrane-permeable analogs of guanosine 3′,5′-cyclic monophosphate (cGMP) prevent disruption of endothelial cell integrity. Because membrane potential ( E m), which influences the electrochemical gradient for Ca2+ influx, is regulated by K+ channels, we investigated the effect of 8-bromo-cGMP on E m and inwardly rectifying K+ (KIR) currents in bovine pulmonary artery and microvascular endothelial cells (BPAEC and BMVEC), using whole cell patch-clamp techniques. Both cell types exhibited inward currents at potentials negative to −50 mV that were abolished by application of 10 μM Ba2+, consistent with KIR current. Ba2+ also depolarized both cell types. 8-Bromo-cGMP (10−3 M) depolarized BPAEC and BMVEC and inhibited KIR current. Pretreatment with Rp-8-cPCT-cGMPS or KT-5823, protein kinase G (PKG) antagonists, did not prevent current inhibition by 8-bromo-cGMP. These data suggest that 8-bromo-cGMP induces depolarization in BPAEC and BMVEC due, in part, to PKG-independent inhibition of KIR current. The depolarization could be a protective mechanism that prevents endothelial cell barrier dysfunction by reducing the driving force for Ca2+ entry.

Two distinct inactivation processes related to phosphorylation in cardiac L-type Ca2+ channel currents

2000 ◽  
Vol 279 (3) ◽  
pp. C603-C610 ◽  
Author(s):  
Sayaka Mitarai ◽  
Muneshige Kaibara ◽  
Katsusuke Yano ◽  
Kohtaro Taniyama
Keyword(s):  
Membrane Potential ◽  
Protein Kinase ◽  
Time Constant ◽  
Kinase Inhibitor ◽  
Slow Component ◽  
Patch Clamp Technique ◽  
Whole Cell Patch Clamp ◽  
Inward Currents ◽  
Inactivation Process ◽  
Channel Currents

We investigated the inactivation process of macroscopic cardiac L-type Ca2+ channel currents using the whole cell patch-clamp technique with Na+ as the current carrier. The inactivation process of the inward currents carried by Na+ through the channel consisted of two components >0 mV. The time constant of the faster inactivating component (30.6 ± 2.2 ms at 0 mV) decreased with depolarization, but the time constant of the slower inactivating component (489 ± 21 ms at 0 mV) was not significantly influenced by the membrane potential. The inactivation process in the presence of isoproterenol (100 nM) consisted of a single component (538 ± 60 ms at 0 mV). A protein kinase inhibitor, H-89, decreased the currents and attenuated the effects of isoproterenol. In the presence of cAMP (500 μM), the inactivation process consisted of a single slow component. We propose that the faster inactivating component represents a kinetic of the dephosphorylated or partially phosphorylated channel, and phosphorylation converts the kinetics into one with a different voltage dependency.

GAT-1 and Reversible GABA Transport in Bergmann Glia in Slices

2002 ◽  
Vol 88 (3) ◽  
pp. 1407-1419 ◽  
Author(s):  
L. Barakat ◽  
A. Bordey
Keyword(s):  
Gaba Receptors ◽  
Receptor Activation ◽  
Bergmann Glia ◽  
Gaba Uptake ◽  
Induced Voltage ◽  
Nipecotic Acid ◽  
Gaba Transporters ◽  
Whole Cell Patch Clamp ◽  
Inward Currents

Although glial GABA uptake and release have been studied in vitro, GABA transporters (GATs) have not been characterized in glia in slices. Whole cell patch-clamp recordings were obtained from Bergmann glia in rat cerebellar slices to characterize carrier-mediated GABA influx and efflux. GABA induced inward currents at −70 mV that could be pharmacologically separated into GABAA receptor and GAT currents. In the presence of GABAA/B/C receptor blockers, mean GABA-induced currents measured −48 pA at −70 mV, were inwardly rectifying between −70 and +50 mV, were inhibited by external Na+ removal, and were diminished by reduction of external Cl−. Nontransportable blockers of GAT-1 (SKF89976-A and NNC-711) and a transportable blocker of all the GAT subtypes (nipecotic acid) reversibly reduced GABA-induced transport currents by 68 and 100%, respectively. A blocker of BGT-1 (betaine) had no effect. SKF89976-A and NNC-711 also suppressed baseline inward currents that likely result from tonic GAT activation by background GABA. The substrate agonists, nipecotic acid and β-alanine but not betaine, induced voltage- and Na+-dependent currents. With Na+ and GABA inside the patch pipette or intracellular GABA perfusion during the recording, SKF89976-A blocked baseline outward currents that activated at −60 mV and increased with more depolarized potentials. This carrier-mediated GABA efflux induced a local accumulation of extracellular GABA detected by GABAA receptor activation on the recorded cell. Overall, these results indicate that Bergmann glia express GAT-1 that are activated by ambient GABA. In addition, GAT-1 in glia can work in reverse and release sufficient GABA to activate nearby GABA receptors.

The mechanism of the releasing action of amphetamine. Uptake, superfusion, and electrophysiological studies on transporter-transfected cells

2000 ◽  
Vol 72 (6) ◽  
pp. 1045-1050 ◽  
Author(s):  
C. Pifl ◽  
H. H Sitte ◽  
H. Reither ◽  
E. A. Singer
Keyword(s):  
Patch Clamp ◽  
Molecular Targets ◽  
Monoamine Transporters ◽  
Transfected Cells ◽  
Whole Cell Patch Clamp ◽  
Sodium Dependent ◽  
Electrophysiological Studies ◽  
Inward Currents ◽  
Vesicular Monoamine Transporters ◽  
The Brain

Amphetamine analogues are able to induce signs of neurotoxicity in the brain. In order to understand this type of neurotoxicity, the interaction of amphetamine with its molecular targets must be elucidated. These molecular targets are plasmalemmal and vesicular monoamine transporters. We investigated the interaction of amphetamine with these transporters in cells transfected with the respective cDNA. Superfusion and whole-cell, patch-clamp experiments were performed, and the toxicity of substrates of the transporters was studied. Amphetamine was taken up by dopamine transporter-expressing cells in a sodium-dependent and cocaine-blockable manner. Furthermore, it elicited inward currents in these cells concentration-dependently. Correlation of uptake, release, and patch-clamp experiments suggest that ion fluxes induced by substrate-gating on transporters may significantly contribute to the releasing action of amphetamine and of other transporter substrates. Dopamine accumulation into serotoninergic terminals depleted of serotonin by 3,4-methylenedioxymethamphetamine was discussed as a mechanism of Ecstasy-toxicity. This is in agreement with a toxic effect of intracellular dopamine which could be demonstrated on our transporter-overexpressing cells. These results, apart from their relevance for the toxicity by amphetamine analogues, may also have bearings on the mechanisms in neurodegenerative diseases affecting monoamine transmitters.

Expression of functional nicotinic acetylcholine receptors in neuroepithelial bodies of neonatal hamster lung

2003 ◽  
Vol 285 (6) ◽  
pp. L1203-L1212 ◽  
Author(s):  
Xiao Wen Fu ◽  
Colin A. Nurse ◽  
Suzanne M. Farragher ◽  
Ernest Cutz
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Respiratory Control ◽  
Hill Coefficient ◽  
Neuroepithelial Bodies ◽  
Patch Clamp Technique ◽  
Nicotinic Acetylcholine ◽  
Whole Cell Patch Clamp ◽  
Inward Currents ◽  
Double Label

Pulmonary neuroepithelial bodies (NEB) are presumed airway chemoreceptors involved in respiratory control, especially in the neonate. Nicotine is known to affect both lung development and control of breathing. We report expression of functional nicotinic acetylcholine receptors (nAChR) in NEB cells of neonatal hamster lung using a combination of morphological and electrophysiological techniques. Nonisotopic in situ hybridization method was used to localize mRNA for the β2-subunit of nAChR in NEB cells. Double-label immunofluorescence confirmed expression of α4-, α7-, and β2-subunits of nAChR in NEB cells. The electrophysiological characteristics of nAChR in NEB cells were studied using the whole cell patch-clamp technique on fresh lung slices. Application of nicotine (∼0.1-100 μM) evoked inward currents that were concentration dependent (EC50 = 3.8 μM; Hill coefficient = 1.1). ACh (100 μM) and nicotine (50 μM) produced two types of currents. In most NEB cells, nicotine-induced currents had a single desensitizing component that was blocked by mecamylamine (50 μM) and dihydro-β-erythroidine (50 μM). In some NEB cells, nicotine-induced current had two components, with fast- and slow-desensitizing kinetics. The fast component was selectively blocked by methyllcaconitine (MLA, 10 nM), whereas both components were inhibited by mecamylamine. Choline (0.5 mM) also induced an inward current that was abolished by 10 nM MLA. These studies suggest that NEB cells in neonatal hamster lung express functional heteromeric α3β2, α4β2, and α7 nAChR and that cholinergic mechanisms could modulate NEB chemoreceptor function under normal and pathological conditions.

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