Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors.
Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors.
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脊髓损伤后肌肉瘫痪的部分原因是脑干衍生的5-羟色胺(5-羟色胺)的丧失，5-羟色胺通常通过调节关键的持久钙电流来维持运动神经元的兴奋性。在这里，我们研究随着时间的推移，运动神经元如何补偿丢失的5-羟色胺来恢复兴奋性。我们发现，在大鼠脊髓横断后几个月，5-HT2C受体mRNA转录后编辑的变化导致5-HT2C受体亚型表达增加，这些亚型是自发活跃的(结构性活性)，而不是5-羟色胺。在缺乏5-羟色胺的情况下，这种结构性受体活性可使运动神经元恢复大的持续钙电流。我们表明，这有助于运动神经元恢复其产生持续肌肉收缩的能力，并最终能够恢复运动功能，如运动。然而，如果没有大脑的调节，这些持续的收缩也会导致虚弱的肌肉痉挛。因此，在大鼠和人中，用SB206553或赛庚啶阻断固有活性的5-HT2C受体，在很大程度上消除了这些钙电流和肌肉痉挛，为抗痉挛药物治疗提供了新的理论基础。
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.