1. Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in [5-HT.sub.2C] receptors
- Author
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Murray, Katherine C., Nakae, Aya, Stephens, Marilee J., Rank, Michelle, D'Amico, Jessica, Harvey, Philip J., Li, Xiaole, Harris, R. Luke W., Ballou, Edward W., Anelli, Roberta, Heckman, Charles J., Mashimo, Takashi, Vavrek, Romana, Sanelli, Leo, Gorassini, Monica A., Bennett, David J., and Fouad, Karim
- Subjects
Neural transmission -- Health aspects -- Research -- Genetic aspects ,Spinal cord injuries -- Complications and side effects -- Research -- Risk factors -- Genetic aspects -- Care and treatment - 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 posttranscriptional editing of [5-HT.sub.2C] receptor mRNA lead to increased expression of [5- HT.sub.2C] 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-HT.sub.2C] 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., Severe spinal cord injury (SCI) causes an immediate paralysis of muscles innervated by motoneurons directly caudal to the injury site. This results not only from a loss of supraspinal tracts [...]
- Published
- 2010
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