Mammalian Locomotor Laboratory, Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden.
BMC Genomics. 2010 Jun 9;11:365. doi: 10.1186/1471-2164-11-365.
Spinal cord injury leads to neurological dysfunctions affecting the motor, sensory as well as the autonomic systems. Increased excitability of motor neurons has been implicated in injury-induced spasticity, where the reappearance of self-sustained plateau potentials in the absence of modulatory inputs from the brain correlates with the development of spasticity.
Here we examine the dynamic transcriptional response of motor neurons to spinal cord injury as it evolves over time to unravel common gene expression patterns and their underlying regulatory mechanisms. For this we use a rat-tail-model with complete spinal cord transection causing injury-induced spasticity, where gene expression profiles are obtained from labeled motor neurons extracted with laser microdissection 0, 2, 7, 21 and 60 days post injury. Consensus clustering identifies 12 gene clusters with distinct time expression profiles. Analysis of these gene clusters identifies early immunological/inflammatory and late developmental responses as well as a regulation of genes relating to neuron excitability that support the development of motor neuron hyper-excitability and the reappearance of plateau potentials in the late phase of the injury response. Transcription factor motif analysis identifies differentially expressed transcription factors involved in the regulation of each gene cluster, shaping the expression of the identified biological processes and their associated genes underlying the changes in motor neuron excitability.
This analysis provides important clues to the underlying mechanisms of transcriptional regulation responsible for the increased excitability observed in motor neurons in the late chronic phase of spinal cord injury suggesting alternative targets for treatment of spinal cord injury. Several transcription factors were identified as potential regulators of gene clusters containing elements related to motor neuron hyper-excitability, the manipulation of which potentially could be used to alter the transcriptional response to prevent the motor neurons from entering a state of hyper-excitability.
脊髓损伤导致神经系统功能障碍，影响运动、感觉和自主神经系统。运动神经元兴奋性的增加与损伤引起的痉挛有关，在没有来自大脑的调节输入的情况下，自我维持的平台电位的再次出现与痉挛的发展相关。
在这里，我们研究了运动神经元对脊髓损伤的动态转录反应，随着时间的推移，它会逐渐发展，以揭示共同的基因表达模式及其潜在的调节机制。为此，我们使用了一种完全脊髓横断的大鼠尾巴模型，导致损伤诱导的痉挛，其中通过激光微切割从标记的运动神经元中获得损伤后 0、2、7、21 和 60 天的基因表达谱。共识聚类确定了 12 个具有不同时间表达谱的基因簇。对这些基因簇的分析确定了早期的免疫/炎症和晚期的发育反应，以及与神经元兴奋性相关的基因的调节，这支持了运动神经元过度兴奋性的发展和平台电位在损伤反应后期的再次出现。转录因子基序分析确定了参与每个基因簇调节的差异表达转录因子，塑造了所识别的生物过程的表达及其与运动神经元兴奋性变化相关的基因。
这项分析为脊髓损伤后期运动神经元中观察到的兴奋性增加的转录调节潜在机制提供了重要线索，表明了治疗脊髓损伤的替代靶点。已经确定了几个转录因子作为包含与运动神经元过度兴奋性相关的元件的基因簇的潜在调节剂，其操纵可能用于改变转录反应，以防止运动神经元进入过度兴奋性状态。
