title: Inflammatory cascades mediate synapse elimination in spinal cord compression.
abstract: BACKGROUND
  Cervical compressive myelopathy (CCM) is caused by chronic spinal cord compression due to spondylosis, a degenerative disc disease, and ossification of the ligaments. Tip-toe walking Yoshimura (twy) mice are reported to be an ideal animal model for CCM-related neuronal dysfunction, because they develop spontaneous spinal cord compression without any artificial manipulation. Previous histological studies showed that neurons are lost due to apoptosis in CCM, but the mechanism underlying this neurodegeneration was not fully elucidated. The purpose of this study was to investigate the pathophysiology of CCM by evaluating the global gene expression of the compressed spinal cord and comparing the transcriptome analysis with the physical and histological findings in twy mice.
  
  
  METHODS
  Twenty-week-old twy mice were divided into two groups according to the magnetic resonance imaging (MRI) findings: a severe compression (S) group and a mild compression (M) group. The transcriptome was analyzed by microarray and RT-PCR. The cellular pathophysiology was examined by immunohistological analysis and immuno-electron microscopy. Motor function was assessed by Rotarod treadmill latency and stride-length tests.
  
  
  RESULTS
  Severe cervical calcification caused spinal canal stenosis and low functional capacity in twy mice. The microarray analysis revealed 215 genes that showed significantly different expression levels between the S and the M groups. Pathway analysis revealed that genes expressed at higher levels in the S group were enriched for terms related to the regulation of inflammation in the compressed spinal cord. M1 macrophage-dominant inflammation was present in the S group, and cysteine-rich protein 61 (Cyr61), an inducer of M1 macrophages, was markedly upregulated in these spinal cords. Furthermore, C1q, which initiates the classical complement cascade, was more upregulated in the S group than in the M group. The confocal and electron microscopy observations indicated that classically activated microglia/macrophages had migrated to the compressed spinal cord and eliminated synaptic terminals.
  
  
  CONCLUSIONS
  We revealed the detailed pathophysiology of the inflammatory response in an animal model of chronic spinal cord compression. Our findings suggest that complement-mediated synapse elimination is a central mechanism underlying the neurodegeneration in CCM.
authors.forename: Morito
authors.initials: M
authors.lastname: Takano
authors.forename: Soya
authors.initials: S
authors.lastname: Kawabata
authors.forename: Yuji
authors.initials: Y
authors.lastname: Komaki
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Shibata
authors.forename: Keigo
authors.initials: K
authors.lastname: Hikishima
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. hidokano@a2.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000235:genetics* / Q000503:physiopathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008279:Magnetic Resonance Imaging; D051379:Mice; D008817:Mice, Mutant Strains; D009069:Movement Disorders / Q000235:genetics / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D013117:Spinal Cord Compression / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D013569:Synapses / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D013997:Time Factors
chemical_list: C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D015922:Complement C1q; D011755:Pyrophosphatases; C021899:nucleotide pyrophosphatase