Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors.
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.
Centre for Neuroscience, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada.
Katherine C
KC
Murray
Aya
A
Nakae
Marilee J
MJ
Stephens
Michelle
M
Rank
Jessica
J
D'Amico
Philip J
PJ
Harvey
Xiaole
X
Li
R Luke W
RL
Harris
Edward W
EW
Ballou
Roberta
R
Anelli
Charles J
CJ
Heckman
Takashi
T
Mashimo
Romana
R
Vavrek
Leo
L
Sanelli
Monica A
MA
Gorassini
David J
DJ
Bennett
Karim
K
Fouad
D000818:Animals; D002118:Calcium / Q000502:physiology; D005260:Female; D006801:Humans; D008124:Locomotion / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D009046:Motor Neurons / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D044348:Receptors, Serotonin, 5-HT2 / Q000502:physiology; D012701:Serotonin / Q000502:physiology; D013035:Spasm / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D015854:Up-Regulation / Q000502:physiology
D020033:Protein Isoforms; D044405:Receptor, Serotonin, 5-HT2C; D044348:Receptors, Serotonin, 5-HT2; D012701:Serotonin; D002118:Calcium