Locomotion After Spinal Cord Injury Depends on Constitutive Activity in Serotonin Receptors

Abstract

Following spinal cord injury (SCI) neurons caudal to the injury are capable of rhythmic locomotor-related activity that can form the basis for substantial functional recovery of stepping despite the loss of crucial brain stem-derived neuromodulators like serotonin (5-HT). Here we investigated the contribution of constitutive 5-HT(2) receptor activity (activity in the absence of 5-HT) to locomotion after SCI. We used a staggered hemisection injury model in rats to study this because these rats showed a robust recovery of locomotor function and yet a loss of most descending axons. Immunolabeling for 5-HT showed little remaining 5-HT below the injury, and locomotor ability was not correlated with the amount of residual 5-HT. Furthermore, blocking 5-HT(2) receptors with an intrathecal (IT) application of the neutral antagonist SB242084 did not affect locomotion (locomotor score and kinematics were unaffected), further indicating that residual 5-HT below the injury did not contribute to generation of locomotion. As a positive control, we found that the same application of SB242084 completely antagonized the muscle activity induced by exogenous application of the 5-HT(2) receptor agonists alpha-methyl-5-HT (IT). In contrast, blocking constitutive 5-HT(2) receptor activity with the potent inverse agonist SB206553 (IT) severely impaired stepping as assessed with kinematic recordings, eliminating most hindlimb weight support and overall reducing the locomotor score in both hind legs. However, even in the most severely impaired animals, rhythmic sweeping movements of the hindlimb feet were still visible during forelimb locomotion, suggesting that SB206553 did not completely eliminate locomotor drive to the motoneurons or motoneuron excitability. The same application of SB206553 had no affect on stepping in normal rats. Thus while normal rats can compensate for loss of 5-HT(2) receptor activity, after severe spinal cord injury rats require constitutive activity in these 5-HT(2) receptors to produce locomotion.

Effects of Serotonergic Medications on Locomotor Performance in Humans with Incomplete Spinal Cord Injury

“…23,24,26 In contrast, however, more recent studies in animal models and humans with SCI indicate that administration with 5HT antagonists may suppress spastic activity 27 as well as volitional strength 28 and locomotor function. 2,29 This is consistent with the suggestion that the presence of spastic motor behaviors may promote the recovery of locomotor activity 30 and the functional use of these involuntary, reflexive mechanisms during locomotion to compensate for volitional weakness.…”

Effects of antidepressant and treadmill gait training on recovery from spinal cord injury in rats

“…We used fluoxetine because it induces production of neurotrophic factors, like serotonin. 11,23 Serotonin receptors are known to be involved in motor recovery and neurotrophic action. 24 Fluoxetine is a selective serotonin reuptake inhibitor, frequently used in patients living with spinal cord injuries who develop psychiatric diseases, particularly depression, in the chronic post-traumatic phase.…”

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

“…Similarly, in mice with SCI, the Basso Mouse Scale demonstrates a return of hind-limb movements by 1 week after thoracic spinal cord transection [10]. The onset for return of spontaneous function in both humans and animals after complete SCI could be due to the restoration of motoneuron excitability by constitutive expression of 5-HT2C receptors [11,12]. Additionally, adaptations in polysynaptic flexor reflexes involved in locomotor circuits [6,13] and synaptic rearrangements may contribute to this first phase of recovery as well [14].…”