Changes in motoneuron properties following spinal cord transection: does afferent input play a role?
Year: 2008
Type: article
Abstract: Spinal cord injury leads to a cascade of pathophysiological events, resulting in simultaneous changes to the morphological, physiological and biochemical characteristics of motor units. It is known that motoneuron properties are altered following spinal cord transection. Such changes include profound increases in the intrinsic excitability of motoneurons, depolarization of resting membrane potential, decreased action potential threshold and shorter after-hyperpolarization (AHP) duration following injury. In addition, brief stimulation can activate the intrinsic voltage-dependent persistent inward currents (PICs) in motoneurons resulting in sustained depolarization and long-lasting firing. The increased excitability may contribute to development of spastic reflexes in spinal patients and animals. It is not known whether these changes in motoneuron properties are dependent on altered afferent input to motoneurons in addition to the loss of descending input. As spastic reflexes do not result from transection of both afferent input and the spinal cord (Harris et al. 2007), it has been hypothesized that preserved afferent input following spinal transection alone plays a role in the development of subsequent spasticity. In order to test this hypothesis, in a recent issue of The Journal of Physiology, Button et al. (2008) characterized and compared the biophysical properties of sciatic motoneurons in rats following either spinal cord transection (ST) or spinal cord isolation (SI), an injury model which involves removal of descending, ascending and afferent input. The group hypothesized that ST and SI would result in different motoneuron properties after injury, which could explain the development of spasticity following ST but not SI. Surprisingly, they found that this is not the case, at least under the conditions of their study. Button et al. (2008) report that, compared to control motoneurons from intact animals, ST and SI motoneurons are more excitable, possessing lower rheobase currents, higher input resistances and increased AHP amplitudes. Further, compared to controls, more ST and SI motoneurons displayed Type 3 and 4 frequency–current (f−I) relationships (the output response for a given input of current), indicative of PIC activation and self-sustained motoneuron firing patterns. Despite this, there was no difference between the PIC amplitudes of control (intact), ST and SI motoneurons. Although no significant difference was found in the f−I relationship of ST and SI motoneurons to 500 ms current, the maximum steady-state firing frequencies of SI motoneurons were lower than controls, but ST motoneurons were not significantly different from controls. This suggests a modest difference between ST and SI groups. SI motoneurons also had higher input resistances than controls, whilst ST motoneurons did not. It should be noted that Button et al. used an extensive analytical protocol in which a variety of basic and active motoneuron properties were measured prior to, and 6–8 weeks after, spinal cord surgery. Few studies have examined such a large range of motoneuron properties, thus making their table of results very informative. Previous studies by members of the group have used the same SI model to study the effects of severe inactivity, reporting that the inactivity triggers elevated rheobase currents, lower AHP amplitudes, depolarized spike thresholds and rightward shifts in f−I relationships. This raises the issue that the authors cannot be sure that the high level of inactivity experienced by the SI animals had no effect on their results and did not confound any changes due to loss of afferent input. The authors do not discuss this point. The group has also examined the effect of increased levels of neuromuscular activity (via exercise) on motoneuron properties. Taken together, the current study, along with previous studies by the group, provides a thorough picture of the biophysical properties of motoneurons following altered levels of neuromuscular activity, ST and SI. As mentioned earlier, there is an important difference between spinal cord transection and deafferentation in patients, the presence of spasticity following ST but not SI. Previous studies have suggested that ongoing neuromuscular activity, such as produced by muscle spasticity, seen in ST but not SI animals, may explain why myofibre atrophy is reversed following chronic ST but remains following SI (Harris et al. 2007). In contrast, the relationship between neuromuscular activity/spasticity and motoneuron size is not known. Biophysical properties indicative of small, fast motoneurons include low rheobase currents and high input resistances. The Button et al. (2008) study reports that rheobase currents and input resistances of motoneurons from both ST and SI animals shift towards that of small motoneurons. However, the authors do not discuss that whilst there was no significant difference in the input resistances of ST and control animals, there was a significant difference between SI and control group values, suggesting a potential difference between SI and ST. Such a difference could be related to greater motoneuron atrophy following SI than ST. Button et al. (2008) report smaller PIC amplitudes following ST than previous studies (Bennett et al. 2001). As they suggest, possible causes of their smaller PIC amplitudes in ST animals are: the location of motoneurons examined, the use of ketamine–xylazine anaesthetic in the Button et al. (2008) study compared with the use of urethane in Bennett (2001b), and the time after injury that recordings were made. Firstly, the site of motoneurons examined by Button et al. (2008) (lumbar region) is different from the site chosen by the bulk of previous studies within the field, the sacral region (Bennett et al. 2001). As Button et al. mention, the muscles supplied by these motoneurons (tail and hindlimb muscles, respectively) have very different functions and thus would be expected to have different motoneuron properties. The biophysical properties of the sciatic nerve are clinically relevant because spasticity of the leg is a barrier to walking in spinal patients. It has been suggested that barbiturate anaesthetics may mask PIC presence or substantially decrease PIC amplitude, therefore partially converting the f−I relationship from a sustained firing (Type 3) to a linear firing (Type 1) pattern (Button et al. 2006). To prevent this, ketamine and xylazine mixtures are often used for in vivo assessment of motoneurons properties. Button et al. suggest that although a larger current is required for spike initiation in ketamine–xylazine anaesthetized rats, the motoneurons are able to maintain large PICs and self sustained firing, both of which enable direct recording of PICs. They base this conclusion on a previous study of their own that compared the PIC amplitude of ketamine–xylazine anaesthetized normal animals to unanaesthetized decerebrate animals, finding no difference (Button et al. 2006). However, had a comparison been made between unanaesthetized decerebrate animals and anaesthetized decerebrate animals, reduced PIC amplitudes may have been evident. The use of ketamine–xylazine anaesthetic in the current Button study may explain the decreased PIC amplitudes reported, compared to previous studies (Bennett et al. 2001), despite larger initiation currents. A further difference between Button et al. (2008) and previous reports is that Button et al. recorded motoneuron properties 6–8 weeks post-injury whereas other studies had longer survival times, typically 1.5–7 months post-injury (Bennett et al. 2001). Bennett et al. have previously reported that PIC amplitudes are small during the initial stage (days) following injury and grow larger with time post-injury (weeks). This is consistent with muscle spasticity developing over time, probably driven by the development of large-amplitude PICs (Bennett et al. 2001). Muscle spasticity is often not developed until after 8 weeks post-injury in rodents. Perhaps Button et al. should have performed EMG recordings on the same animals to ascertain whether the animals had the typical muscle responses of chronic spinally injured animals (i.e. high EMG activity). In comparison, Harris et al. (2007) have previously reported that following spinal isolation, whilst contractile activity of the muscle is absent, motoneurons occasionally produce low-amplitude spontaneous bursts of muscle EMG activity, indicating that the motoneurons rest close to threshold levels. Another factor modifying excitability is AHP. Other studies have reported that ST leads to decreased AHP decay time compared to SI (Czeh et al. 1978) whereas Button et al. report that ST, SI and intact animals all have similar AHP decay times. Czeh et al. have previously reported that the duration of the after-hyperpolarization decreases with time post-injury (weeks) and thus recording motoneuron properties too soon following ST may have resulted in missing this alteration as well. In conclusion, if Button et al. (2008) had allowed a longer time post-injury the animals may have developed greater muscle spasticity and greater PIC amplitudes than SI animals, resulting in a different conclusion. To resolve the issue it would be important to have additional data at longer survival times to ascertain that chronicity is complete and that the motoneurons have fully undergone any transection-induced changes. Nevertheless, the outcome of the current study is that motoneuron properties are not affected by afferent input. It is a significant outcome because it goes against previous ideas. It heralds the need for further examination of motoneuron properties following spinal transection, which may lead to exciting new interventions to help spinally injured patients.
Source: The Journal of Physiology
Authors: A. S. Laird, A. Wu, J. L. Lauschke
Institution: UNSW Sydney
Language: English
Topic: Spinal Cord Injury Research
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1972092524