The role of the serotonergic system in locomotor recovery after spinal cord injury

Abstract

Serotonin (5-HT), a monoamine neurotransmitter synthesized in various populations of brainstem neurons, plays an important role in modulating the activity of spinal networks involved in vertebrate locomotion. Following spinal cord injury (SCI) there is a disruption of descending serotonergic projections to spinal motor areas, which results in a subsequent depletion in 5-HT, the dysregulation of 5-HT transporters as well as the elevated expression, super-sensitivity and/or constitutive auto-activation of specific 5-HT receptors. These changes in the serotonergic system can produce varying degrees of locomotor dysfunction through to paralysis. To date, various approaches targeting the different components of the serotonergic system have been employed to restore limb coordination and improve locomotor function in experimental models of SCI. These strategies have included pharmacological modulation of serotonergic receptors, through the administration of specific 5-HT receptor agonists, or by elevating the 5-HT precursor 5-hydroxytryptophan, which produces a global activation of all classes of 5-HT receptors. Stimulation of these receptors leads to the activation of the locomotor central pattern generator (CPG) below the site of injury to facilitate or improve the quality and frequency of movements, particularly when used in concert with the activation of other monoaminergic systems or coupled with electrical stimulation. Another approach has been to employ cell therapeutics to replace the loss of descending serotonergic input to the CPG, either through transplanted fetal brainstem 5-HT neurons at the site of injury that can supply 5-HT to below the level of the lesion or by other cell types to provide a substrate at the injury site for encouraging serotonergic axon regrowth across the lesion to the caudal spinal cord for restoring locomotion.

Prior Treatment with Anti-High Mobility Group Box-1 Antibody Boosts Human Neural Stem Cell Transplantation-Mediated Functional Recovery After Spinal Cord Injury

“…4D). Although we cannot currently distinguish whether increased numbers of 5‐HT serotonergic fibers in anti‐HMGB1 mAb treatment groups were attributable to the retention of pre‐existing fibers or to newly sprouted fibers after injury, these data suggest that anti‐HMGB1 mAb treatment led to an increase in 5‐HT‐positive fibers in the spinal cord after injury, resulting in functional recovery as was observed in previous studies .…”

BDNF Overexpression Exhibited Bilateral Effect on Neural Behavior in SCT Mice Associated with AKT Signal Pathway

“…More important, both our results of BMS score and other report were consistent with this change. Ghosh M in turn confirmed this view, following SCI, there was a disruption of descending serotonergic projections to spinal motor areas, which resulted in a subsequent depletion in 5-HT [36]. These demonstrated that 5-HT played an important role in modulating the activity of spinal networks involved in vertebrate locomotion.…”

Tubular scaffold with microchannels and an H‐shaped lumen loaded with bone marrow stromal cells promotes neuroregeneration and inhibits apoptosis after spinal cord injury

“…The raphespinal axon is the main nerve fibre mediating locomotor function in the spinal cord (Ghosh & Pearse, ). Serotonin (5‐HT) is a neurotransmitter specifically transmitted by raphespinal axons in the spinal cord.…”