Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT<sub>1B</sub> and 5-HT<sub>1F</sub> receptors

Murray, Katherine C.; Stephens, Marilee J.; Rank, Michelle M; D’Amico, Jessica M.; Gorassini, Monica A.; Bennett, David J.

doi:10.1152/jn.01011.2010

Cited by 53 publications

(88 citation statements)

References 80 publications

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“…Indeed, the absence of anesthesia most likely allowed otherwise quiescent spinal networks to be active and participate in the modulation of membrane conductance, affecting motoneuronal responsiveness (Harvey et al,2006a, b, Li et al,2006, Murray et al,2010 see also (D'Amico et al,2014). However, slowly-activated currents, like persistent inward currents, required long-duration input and could not be fully actuated by brief stimulations like the ones used in our study (Murray et al,2011).…”

Section: The Absence Of Anesthesia and Reversal From Inhibitory To Exmentioning

confidence: 92%

Effect of buspirone on the H-reflex in acute spinal decerebrated mice

Develle¹,

Leblond²

2018

Preprint

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2 KEY POINTS SUMMARY Buspirone, a partial serotoninergic agonist (5HT1A), exerts a considerable acute facilitation of spinally-mediated locomotion after a complete spinal lesion in mice.  Since locomotion is associated with reflex modulation, we focused in this study on the effect of buspirone on H-reflex in acute spinal mice after decerebration and removal of anesthesia.  Buspirone injection resulted in a depression of the H-reflex during the first 20 minutes followed, 40 minutes later, by an increase of the reflex.  The H-reflex increase is not due to a disinhibition since buspirone had no effect on the frequency dependent depression (FDD) of the H-reflex.  The use of a model of adult decerebrate mouse with complete spinal cord injury allows to establish that buspirone has a biphasic effect on the H-reflex and that the inhibitory action on sensory information concurs with an excitatory action on locomotion.3 ABSTRACT Pharmacological treatment facilitating locomotor expression also modulates reflex expression through the re-arrangement of spinal networks. Buspirone, a partial serotonin receptor agonist (5-HT1A), was recently shown to facilitate and even trigger locomotor movements in mice after complete spinal lesion (Tx). Here, we studied its effect on the Hreflex after acute Tx in adult mice. To avoid possible impacts of anesthetics on H-reflex depression, experiments were performed after decerebration in un-anesthetized mice (N=13).The H-reflex in plantar muscles of the hind-paw was recorded after tibial nerve stimulation 2 h after Tx at the 8 th thoracic vertebrae. Average H/M ratio was compared before and every 10 min after buspirone (8 mg/kg, i.p.) for 60 min. Frequency-dependent depression (FDD)of the H-reflex was assessed before and 50 min after buspirone. Before buspirone, a stable H-reflex could be elicited in acute spinal mice and FDD of the H-reflex was observed at 5Hz (68%) and 10Hz (70%) relative to 0.2Hz. After buspirone, the H/M ratio was initially significantly decreased to 69% of pre-treatment. It then increased significantly 30 to 60 min after exposure to buspirone, reaching 170% 60 min after injection. FDD 50 min after buspirone was not significantly different that FDD without treatment. Altogether results suggest that the reported pro-locomotor effect of buspirone occurs at a time where there is a reflex depression followed by a second phase marked by enhancement of reflex excitability, denoting functional inhibitory control. Abbreviations: 5-HT: 5-Hydroxytryptamine; 5-HT1A: 1A subunit in 5-Hydroxytryptamine receptor; 8-OHDPAT: 8-Hydroxy-2-DI-n-Propylamino-Tetraline; CPG Central Pattern Generator; EMG: electromyographic; FDD: Frequency Dependent Depression; GABA: Gamma-Aminobutyric-Acid; TASK-1 acid-sensitiv-K-1; Tx: complete transection. Antri M, Mouffle C, Orsal D, and Barthe J. 5-HT 1A receptors are involved in short-and long-term processes responsible for 5-HT-induced locomotor function recovery in chronic spinal rat. Eur J Neurosci 18: 1963-1972, 2003. Barbeau H and Rossignol S. Re...

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Section: The Absence Of Anesthesia and Reversal From Inhibitory To Exmentioning

confidence: 92%

Effect of buspirone on the H-reflex in acute spinal decerebrated mice

Develle¹,

Leblond²

2018

Preprint

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“…An exaggerated monosynaptic reflex is characteristic of SCI and is thought to contribute to the production of clonus and hyperreflexia (Nielsen et al, 2007). In addition to exaggerated phasic responses, long-lasting responses can also be present (Bennett et al, 1999;Bennett et al, 2004;Li et al, 2004;Murray et al, 2011b) and contribute to triggering spasms in SCI patients (Norton et al, 2008).…”

Section: Clp257 Reduces the Phasic And Tonic Stretch-induced Emg Respmentioning

confidence: 99%

“…In our experiments, slow stretches of the triceps surae elicited no EMG activity in SCI animals, whereas high velocity stretches evoked both large phasic monosynaptic EMG responses, as well as long lasting tonic activity. While exaggerated monosynaptic reflexes contribute to clonus and hyperreflexia (Bennett et al, 1996;De Serres et al, 2002), the long-lasting responses are thought to contribute to hypertonia and initiation of spasms (Bennett et al, 1999;Li et al, 2004;Murray et al, 2011b). CLP257 significantly reduced both the phasic and tonic responses, suggesting an effect on multiple spinal pathways that contribute to spasticity (Murray et al, 2010;2011a;D'Amico et al, 2013a-b;.…”

Section: Enhancing Kcc2 Decreases Hyperreflexia After Chronic Scimentioning

confidence: 99%

Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic SCI

Bilchak

Yeakle

Caron

et al. 2020

Preprint

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After spinal cord injury (SCI), the majority of individuals develop spasticity, a debilitating condition involving involuntary movements, co-contraction of antagonistic muscles, and hyperreflexia. By acting on GABAergic and Ca2+-dependent signaling, current anti-spastic medications lead to serious side effects, including a drastic decrease in motoneuronal excitability which impairs motor function and rehabilitation efforts. Exercise, in contrast, decreases spastic symptoms without decreasing motoneuron excitability. These functional improvements coincide with an increase in expression of the chloride co-transporter KCC2 in lumbar motoneurons. Thus, we hypothesized that spastic symptoms can be alleviated directly through restoration of chloride homeostasis and endogenous inhibition by increasing KCC2 activity. Here, we used the recently developed KCC2 enhancer, CLP257, to evaluate the effects of acutely increasing KCC2 extrusion capability on spastic symptoms after chronic SCI. Sprague Dawley rats received a spinal cord transection at T12 and were either bike-trained or remained sedentary for 5 weeks. Increasing KCC2 activity in the lumbar enlargement improved the rate-dependent depression of the H-reflex and reduced both phasic and tonic EMG responses to muscle stretch in sedentary animals after chronic SCI. Furthermore, the improvements due to this pharmacological treatment mirror those of exercise. Together, our results suggest that pharmacologically increasing KCC2 activity is a promising approach to decrease spastic symptoms in individuals with SCI. By acting to directly to restore endogenous inhibition, this strategy has potential to avoid severe side effects and improve the quality of life of affected individuals.Significance StatementSpasticity is a condition that develops after spinal cord injury (SCI) and causes major complications for individuals. We have previously reported that exercise attenuates spastic symptoms after SCI through an increase in expression of the chloride co-transporter KCC2, suggesting that restoring chloride homeostasis contributes to alleviating spasticity. However, the early implementation of rehabilitation programs in the clinic is often problematic due to co-morbidities. Here, we demonstrate that pharmacologically enhancing KCC2 activity after chronic SCI reduces multiple signs of spasticity, without the need for rehabilitation.

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“…As calcium persistent inward current is not always recruited in these motoneurons, muscle spasms are weaker (Murray et al . , D'Amico et al . ).…”

Section: Involuntary Contractions Are Common In Muscles Paralysed Bymentioning

confidence: 99%

Human spinal cord injury: motor unit properties and behaviour

et al. 2013

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Spinal cord injury (SCI) results in widespread variation in muscle function. Review of motor unit data shows that changes in the amount and balance of excitatory and inhibitory inputs after SCI alter management of motoneurons. Not only are units recruited up to higher than usual relative forces when SCI leaves few units under voluntary control, the force contribution from recruitment increases due to elevation of twitch/tetanic force ratios. Force gradation and precision are also coarser with reduced unit numbers. Maximal unit firing rates are low in hand muscles, limiting voluntary strength, but are low, normal or high in limb muscles. Unit firing rates during spasms can exceed voluntary rates, emphasizing that deficits in descending drive limit force production. SCI also changes muscle properties. Motor unit weakness and fatigability seem universal across muscles and species, increasing the muscle weakness that arises from paralysis of units, motoneuron death and sensory impairment. Motor axon conduction velocity decreases after human SCI. Muscle contractile speed is also reduced, which lowers the stimulation frequencies needed to grade force when paralysed muscles are activated with patterned electrical stimulation. This slowing does not necessarily occur in hind limb muscles after cord transection in cats and rats. The nature, duration and level of SCI underlie some of these species differences, as do variations in muscle function, daily usage, tract control and fibre-type composition. Exploring this diversity is important to promote recovery of the hand, bowel, bladder and locomotor function most wanted by people with SCI.

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Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT_1B and 5-HT_1F receptors

Cited by 53 publications

References 80 publications

Effect of buspirone on the H-reflex in acute spinal decerebrated mice

Effect of buspirone on the H-reflex in acute spinal decerebrated mice

Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic SCI

Human spinal cord injury: motor unit properties and behaviour

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Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F receptors

Cited by 53 publications

References 80 publications

Effect of buspirone on the H-reflex in acute spinal decerebrated mice

Effect of buspirone on the H-reflex in acute spinal decerebrated mice

Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic SCI

Human spinal cord injury: motor unit properties and behaviour

Contact Info

Product

Resources

About

Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT_1B and 5-HT_1F receptors