title: Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus.
abstract: BACKGROUND
  Normal-pressure hydrocephalus (NPH) is a neurodegenerative disorder that usually occurs late in adult life. Clinically, the cardinal features include gait disturbances, urinary incontinence, and cognitive decline.
  
  
  RESULTS
  Herein we report the characterization of a novel mouse model of NPH (designated p23-ST1), created by N-ethyl-N-nitrosourea (ENU)-induced mutagenesis. The ventricular size in the brain was measured by 3-dimensional micro-magnetic resonance imaging (3D-MRI) and was found to be enlarged. Intracranial pressure was measured and was found to fall within a normal range. A histological assessment and tracer flow study revealed that the cerebral spinal fluid (CSF) pathway of p23-ST1 mice was normal without obstruction. Motor functions were assessed using a rotarod apparatus and a CatWalk gait automatic analyzer. Mutant mice showed poor rotarod performance and gait disturbances. Cognitive function was evaluated using auditory fear-conditioned responses with the mutant displaying both short- and long-term memory deficits. With an increase in urination frequency and volume, the mutant showed features of incontinence. Nissl substance staining and cell-type-specific markers were used to examine the brain pathology. These studies revealed concurrent glial activation and neuronal loss in the periventricular regions of mutant animals. In particular, chronically activated microglia were found in septal areas at a relatively young age, implying that microglial activation might contribute to the pathogenesis of NPH. These defects were transmitted in an autosomal dominant mode with reduced penetrance. Using a whole-genome scan employing 287 single-nucleotide polymorphic (SNP) markers and further refinement using six additional SNP markers and four microsatellite markers, the causative mutation was mapped to a 5.3-cM region on chromosome 4.
  
  
  CONCLUSIONS
  Our results collectively demonstrate that the p23-ST1 mouse is a novel mouse model of human NPH. Clinical observations suggest that dysfunctions and alterations in the brains of patients with NPH might occur much earlier than the appearance of clinical signs. p23-ST1 mice provide a unique opportunity to characterize molecular changes and the pathogenic mechanism of NPH.
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Lee
authors.forename: Ching-Pang
authors.initials: CP
authors.lastname: Chang
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Lee
authors.forename: Yi-Chih
authors.initials: YC
authors.lastname: Wu
authors.forename: Hsu-Wen
authors.initials: HW
authors.lastname: Tseng
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: Tung
authors.forename: Min-Tzu
authors.initials: MT
authors.lastname: Wu
authors.forename: Yen-Hui
authors.initials: YH
authors.lastname: Chen
authors.forename: Lu-Ting
authors.initials: LT
authors.lastname: Kuo
authors.forename: Dennis
authors.initials: D
authors.lastname: Stephenson
authors.forename: Shuen-Iu
authors.initials: SI
authors.lastname: Hung
authors.forename: Jer-Yuarn
authors.initials: JY
authors.lastname: Wu
authors.forename: Chen
authors.initials: C
authors.lastname: Chang
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D003072:Cognition Disorders / Q000175:diagnosis; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006850:Hydrocephalus, Normal Pressure / Q000175:diagnosis / Q000378:metabolism*; D007427:Intracranial Pressure; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009048:Motor Skills; D016296:Mutagenesis; D020641:Polymorphism, Single Nucleotide
chemical_list: D005038:Ethylnitrosourea