Abstract
BackgroundSpinal 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.ResultsHere 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.ConclusionsThis 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.
Highlights
Spinal cord injury leads to neurological dysfunctions affecting the motor, sensory as well as the autonomic systems
To investigate the molecular mechanisms underlying the reappearance of plateau potentials after spinal cord injury we recently undertook a global gene expression study of motor neurons in the late phase of injuryinduced spasticity [25] using the rat-tail-model with a complete spinal cord transection at the S2 segment, developed by Bennett and coworkers [6]
Transcriptional response of motor neurons to injury Spinal cord injury was inflicted by a complete spinal cord transection at the second sacral segment (S2), in effect disconnecting the spinal networks caudal to the lesion from the remaining part of the central nervous system
Summary
Spinal cord injury leads to neurological dysfunctions affecting the motor, sensory as well as the autonomic systems. In the present work we investigate the dynamic transcriptional response of motor neurons following spinal cord injury 0, 2, 7, 21 and 60 days post injury, enabling us to dissect out some of the regulatory mechanisms of transcription underlying the observed hyper-excitability. In the brain, such dynamic transcriptome analyses have been used to analyze the gene expression pattern of well-defined cell populations during development [26,27]. In the present study the transcriptional response of motor neurons over time constitute a direct measure of cell-specific processes in a complex anatomical structure, allowing us in a similar fashion to examine the expression patterns and the underlying regulatory mechanisms of this response
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