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

• Published in: Nature medicine Vol. 16; no. 6; pp. 694 - 700
• Main Authors: 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, Fouad, Karim
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2010; Nature Publishing Group
• Subjects: 631/378/1687/1825; 631/378/2632/1664; 631/92/612/194; Animals; Biomedical and Life Sciences; Biomedicine; Calcium; Calcium - physiology; Cancer Research; Female; Humans; Infectious Diseases; Locomotion - physiology; Membrane Potentials - physiology; Metabolic Diseases; Molecular Medicine; Motor Neurons - physiology; Neurosciences; Neurotransmitters; Paralysis; Protein Isoforms - physiology; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C - physiology; Receptors, Serotonin, 5-HT2 - physiology; Rodents; Serotonin - physiology; Spasm - physiopathology; Spinal cord injuries; Spinal Cord Injuries - physiopathology; Up-Regulation - physiology
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2160

Spinal cord injury leads to flaccid paralysis resulting from the loss of descending serotonergic modulation. Murray et al . demonstrate that spontaneous recovery of motoneuron excitability is associated with alternative mRNA editing and increased expression of constitutively active 5HT 2C serotonin receptors. Activation of these receptors leads to large persistent calcium currents, sustained muscle contractions and restoration of locomotion. However, in the absence of descending modulation from the brain, this leads to spasticity. Inhibiting constitutive 5-HT receptor activity is effective in reducing spasticity in rats and humans following spinal cord injury. 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-HT 2C receptor mRNA lead to increased expression of 5-HT 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 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.