Chapter 21 Possible functions of transmitter-controlled plateau potentials in α motoneurones

doi:10.1016/S0079-6123(08)62219-0

Progress in Brain Research

Volume 80, 1989, Pages 257-267

https://doi.org/10.1016/S0079-6123(08)62219-0 Get rights and content

An increasing number of vertebrate central neurones has been shown to possess complex membrane properties. However, the functional significance of such properties is unclear. The aim of the present paper is to review some old and new findings in this field from this laboratory. First, a bistability in α motoneurones in reduced preparations is described. Thereafter we present some new data on a bistable behaviour in motor units in unrestrained intact animals during posture. Finally, the possible role of motoneuronal bistability in locomotion and in spasticity is discussed. Recently a bistable firing behaviour in motoneurones was described in the unanaesthetized decerebrate cat. This behaviour is generated by a plateau potential, which causes long-lasting excitability increase and can be initiated and terminated by short-lasting synaptic excitation and inhibition respectively, and is contingent upon activity in descending noradrenergic and serotonergic systems. In an in vitro preparation of the turtle spinal cord the plateau potential was shown to be serotonin dependent and generated by a voltage-dependent non-inactivating calcium conductance. In order to elucidate possible functional consequences of a bistable firing behaviour in the intact animal, the firing pattern of individual soleus motor units was studied by means of chronic EMG registration in awake unrestrained rats during quiet standing. Implanted electrodes allowed the delivery of excitatory and inhibitory stimulus trains to the motoneurones. It was found that short-lasting synaptic stimulation could induce maintained shifts between two stable levels of motoneurone firing frequencies, as in the decerebrate cat. Spontaneous shifts between the same two levels were also present. It seems most likely that plateau potentials are responsible for this bistable firing property in intact animals. The role of plateau potentials in locomotion is difficult to study. At present there are no clear indications of the utilization of plateau potentials in locomotion in intact animals. However, “clamped frequency” bursts which are observed in fictive locomotion in spinal cats might be explained by plateaus. The existence of plateau potentials in motoneurones may also be of importance in spasticity. Therefore, the development of spasticity in two spinalized cats was followed for 3 weeks. Acute experiments demonstrated plateau potentials in some motoneurones in this preparation.

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In models of spinal cord injury it is now well documented that hyperreflexia and spasticity appear as a consequence of increased motoneurone excitability in addition to local changes in spinal cord circuitry. This includes a reduction of inhibition (Norton et al., 2008), reductions in post-activation depression of excitatory Ia afferent synapses on motoneurones (Schindler-Ivens and Shields, 2000), increases in Na+ and Ca2+ PICs (Eken et al., 1989; Murray et al., 2010; Bellardita et al., 2017), and an upregulation or constitutive activity of serotonergic and noradrenergic receptors (Murray et al., 2010; Rank et al., 2011). Spasticity is also observed in SOD1 models of ALS (Dentel et al., 2013; Modol et al., 2014), and many of the changes observed following spinal cord injury have also been observed in SOD1 models, including the G127X.
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However, using conditioning H-reflex protocols to measure changes in postactivation depression, reciprocal inhibition, presynaptic inhibition, and Renshaw cell inhibition within the Ia afferent-alpha motoneuron pathway may provide insights on neural adaptations that occur after SMT for patients with LBP.24,25 Reliable and valid cat models that are being used to study the effects of SM on afferent discharges may be extended to study the mechanistic relationship among bistability properties of motoneuron membranes, hypertonicity, and SM-like loads.19,36-39 Experimental models to induce and interrupt muscle cramps in humans may also provide insights on the mechanistic relationship among bistability properties of motoneuron membranes from motor unit discharge rates, hypertonicity, and HVLA SM.40-42
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Asymptomatic adults (n = 66) and patients with subacute LBP (n = 45) were randomized into 3 lumbosacral procedures: side-posture positioning, joint preloading with no thrust, and HVLA SM. A time series of 40 H_max/M_max ratios at a rate of 0.1 Hz were recorded in blocks of 10 trials at baseline and after the lumbosacral procedures at time points corresponding to immediately after, 5 minutes after, and 10 minutes after the procedure. Descriptive time series analysis techniques included time plots, outlier detection, and autocorrelation functions. A mixed analysis of variance model (group × procedure × time) was used to compare the effects of lumbosacral procedures on H_max/M_max ratios between the patients with subacute LBP and asymptomatic participants.
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The hyperreflexia, in the chronic phase, is characterized by exaggerated cutaneous reflexes and velocity-dependent stretch reflexes, also termed spasticity (Lance, 1980; Dietz, 2000; Nielsen et al., 2007). Experiments in cats (Eken et al., 1989) and rats (Bennett et al., 1999, 2001a,b; Li et al., 2004) have suggested that the appearance of plateau potentials generated by persistent inward currents (PICs) in motoneurons is one of the mechanisms underlying the hyperexcitability observed in the chronic spinal phase. In a rat model with a complete transection at sacral 2 (S2) level Bennett and colleagues have demonstrated that the magnitude of PICs in motoneurons below the lesion is increased and the motoneurons become 30-fold supersensitive to 5-HT or 5-HT2A/C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (Harvey et al., 2006a; Li et al., 2007).
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The time course of serotonin 2A receptor expression after spinal transection of rats: An immunohistochemical study
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In both cases the tonic/maintained discharge also seems to be dependent on the recruitment of plateau potentials in the motoneurons (Crone et al., 1988; Hounsgaard et al., 1988). The return of tonic stretch reflexes (and general hyper-reflexia) following a chronic spinal transection (>2 weeks) has been related to the return of plateau potentials in motoneurons–but now without the descending serotonergic innervation (see Eken et al., 1989; Bennett et al., 2001a,b). There may be several reasons for the return of plateau potentials and the development of a spastic syndrome.
Hyperexcitability of motoneurons is one of the key mechanism that has been demonstrated to underlie the pathogenesis of spasticity after spinal injury. Serotonin (5-HT) denervation supersensitivity is one of the mechanisms underlying this increased motoneuron excitability. In this study, to examine whether the supersensitivity is caused by 5-HT receptor upregulation we investigated changes in levels of 5-HT2A receptor immunoreactivity (5-HT2AR-IR) following a spinal transection in the sacral spinal cord of rats at seven different time points post injury: 2, 8, 16 h, and 1, 2, 7 and 28 days, respectively. 5-HT2AR-IR density was analyzed in motoneurons (regions containing their somata and dendrites) in the spinal segments below the lesion. The results showed no significant changes in 5-HT2AR-IR in the motoneurons up to 16 h following the transection. After 1-day, however the levels of 5-HT2AR-IR increased in the motoneurons and their dendrites, with the density level being 3.4-fold higher in spinalized rats than in sham-operated rats. The upregulation increased progressively until a maximal level was reached at 28 days post-injury. We also investigated 5-HT and 5-HT transporter expressions at five different post injury time points: 1, 2, 7, 21 and 60 days and they showed concurrent down-regulation changes after 2 days. These results suggest that the upregulation of 5-HT2ARs may at least partly underlie the development of 5-HT denervation supersensitivity in spinal motoneurons following spinal injury and thereby implicates their involvement in the pathogenesis of the subsequent development of spasticity.

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Chapter 21 Possible functions of transmitter-controlled plateau potentials in α motoneurones

Prog. Neurobiol.

Brain Res.

Brain Res.

Brain Res.

Neuropharmacology

The time course of the disappearance of noradrenaline and 5-hydroxytryptamine in the spinal cord after transection

Acta Physiol. Scand.

The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network

Science

Response of muscle spindle primary endings to static stretch in acute and chronic spinal cats

Am. J. Vet. Res.

Plateau potentials in α-motoneurones induced by intravenous injection of L-DOPA and clonidine in the spinal cat

J. Physiol. (London)

Tonic stretch reflexes and their dependence of polysynaptic excitation from muscle spindle Ia afferents

Maintained changes in motoneuronal excitability by short-lasting synaptic inputs in the decerebrate cat

J. Physiol. (London)

Central generation of locomotion in vertebrates

Bistable firing properties of soleus motor units in freely moving rats

Acta Physiol. Scand.

Bi-stable firing pattern of soleus motor units in rats during quiet standing

J. Physiol. (London)

Firing patterns of motor units in normal rats

Nature (London)

Cat hindlimb motoneurones during locomotion. II. Normal activity patterns

J. Neurophysiol.