Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors

Abstract

Muscle paralysis after spinal cord injury is partly caused by a loss of brainstem-derived serotonin (5-HT), which normally maintains motoneuron excitability by regulating crucial persistent calcium currents. Here we examine how over time motoneurons compensate for lost 5-HT to regain excitability. We find that, months after a spinal transection in rats, changes in post-transcriptional editing of 5-HT2C receptor mRNA lead to increased expression of 5-HT2C receptor isoforms that are spontaneously active (constitutively active) without 5-HT. Such constitutive receptor activity restores large persistent calcium currents in motoneurons in the absence of 5-HT. We show that this helps motoneurons recover their ability to produce sustained muscle contractions and ultimately enables recovery of motor functions such as locomotion. However, without regulation from the brain, these sustained contractions can also cause debilitating muscle spasms. Accordingly, blocking constitutively active 5-HT2C receptors with SB206553 or cyproheptadine, in both rats and humans, largely eliminates these calcium currents and muscle spasms, providing a new rationale for antispastic drug therapy.

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].…”

Divergent Modulation of Clinical Measures of Volitional and Reflexive Motor Behaviors following Serotonergic Medications in Human Incomplete Spinal Cord Injury

“…1 The SCI disease progression results in structural changes to these 5-HT receptors in the chronic stages post-injury, allowing for PIC activation with minimal residual descending 5-HT. [2][3][4] Dysregulation of PIC activation contributes to the presence of both spasticity and spasms; accordingly, medications that block 5-HT activity may decrease spasticity/spasms, 3 whereas medications that augment 5-HT bioavailability may increase spasticity/spasms. 5 Volitional motor output may also be dependent on motoneuron PIC activity.…”

“…For example, PIC activation may help explain the observations of increased time to task failure during sustained motor activity and increases in peak volitional torque generation during maximal effort contractions in patients with incomplete SCI. [8][9][10] Further, medications that decrease 5-HT may decrease volitional strength and functional performance following SCI, 3,11 whereas preliminary data suggest that medications thataugment 5-HT may increase strength.…”

Integration and Long Distance Axonal Regeneration in the Central Nervous System from Transplanted Primitive Neural Stem Cells

“…In particular, their neural tissue integration and differentiation into serotonergic neurons have a broad implication for psychiatric and somatic therapies. Serotonergic fibers within the spinal cord regulate pain perception, locomotion, and autonomic functions (23)(24)(25). The most devastating consequence of spinal cord injury is the loss of function distal to the lesion.…”