Degeneration of serotonergic neurons in amyotrophic lateral sclerosis: a link to spasticity
Degeneration of serotonergic neurons in amyotrophic lateral sclerosis: a link to spasticity
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DOI：
10.1093/brain/aws274
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发表时间：
2013-02-01
期刊：
影响因子：
14.5
通讯作者：
Dupuis, Luc
中科院分区：
文献类型：
--
作者：
Dentel, Christel;Palamiuc, Lavinia;Dupuis, Luc
痉挛是中枢神经系统疾病患者常见的致残症状，包括肌萎缩侧索硬化症，一种同时影响上运动神经元和下运动神经元的疾病。在肌萎缩侧索硬化症中，痉挛传统上被认为是大脑皮层上运动神经元退化的结果，尽管其他神经元类型的退化，特别是5-羟色胺能神经元的退化也可能是痉挛的原因之一。我们对7名肌萎缩侧索硬化症患者和6名对照组进行了病理学研究，观察到肌萎缩侧索硬化症患者的中枢5-羟色胺能神经元经历了一个变性过程，伴有明显的神经元性变性，有时还会出现胞体丢失。此外，在肌萎缩侧索硬化症患者中，远端5-羟色胺能投射到脊髓运动神经元和海马区系统性退化。在转基因肌萎缩侧索硬化症模型SOD1(G86R)小鼠中，在出现运动症状之前，脑干和脊髓中的5-羟色胺水平降低。此外，发病时5-羟色胺神经元胞体明显萎缩，并伴有神经元性变性。我们假设5-羟色胺能神经元的变性可能是肌萎缩侧索硬化症痉挛的基础，并在体内使用机械刺激反应的尾肌痉挛样收缩作为痉挛的衡量标准来研究这一假说。SOD1(G86R)小鼠尾肌末期出现痉挛样收缩。重要的是，它们被5-羟色胺-2b/c受体反向激动剂取消。与此相一致的是，5-羟色胺-2b受体的表达在发病时显著增加。总之，我们发现5-羟色胺能神经元在肌萎缩侧索硬化症期间退化，这可能是小鼠痉挛的基础。5-羟色胺-2b/c受体的反向激动剂是否对治疗肌萎缩侧索硬化症患者的痉挛有兴趣，还需要进一步的研究。
Spasticity is a common and disabling symptom observed in patients with central nervous system diseases, including amyotrophic lateral sclerosis, a disease affecting both upper and lower motor neurons. In amyotrophic lateral sclerosis, spasticity is traditionally thought to be the result of degeneration of the upper motor neurons in the cerebral cortex, although degeneration of other neuronal types, in particular serotonergic neurons, might also represent a cause of spasticity. We performed a pathology study in seven patients with amyotrophic lateral sclerosis and six control subjects and observed that central serotonergic neurons suffer from a degenerative process with prominent neuritic degeneration, and sometimes loss of cell bodies in patients with amyotrophic lateral sclerosis. Moreover, distal serotonergic projections to spinal cord motor neurons and hippocampus systematically degenerated in patients with amyotrophic lateral sclerosis. In SOD1 (G86R) mice, a transgenic model of amyotrophic lateral sclerosis, serotonin levels were decreased in brainstem and spinal cord before onset of motor symptoms. Furthermore, there was noticeable atrophy of serotonin neuronal cell bodies along with neuritic degeneration at disease onset. We hypothesized that degeneration of serotonergic neurons could underlie spasticity in amyotrophic lateral sclerosis and investigated this hypothesis in vivo using tail muscle spastic-like contractions in response to mechanical stimulation as a measure of spasticity. In SOD1 (G86R) mice, tail muscle spastic-like contractions were observed at end-stage. Importantly, they were abolished by 5-hydroxytryptamine-2b/c receptors inverse agonists. In line with this, 5-hydroxytryptamine-2b receptor expression was strongly increased at disease onset. In all, we show that serotonergic neurons degenerate during amyotrophic lateral sclerosis, and that this might underlie spasticity in mice. Further research is needed to determine whether inverse agonists of 5-hydroxytryptamine-2b/c receptors could be of interest in treating spasticity in patients with amyotrophic lateral sclerosis.