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Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus.

Publication ,  Journal Article
Lee, M-J; Chang, C-P; Lee, Y-H; Wu, Y-C; Tseng, H-W; Tung, Y-Y; Wu, M-T; Chen, Y-H; Kuo, L-T; Stephenson, D; Hung, S-I; Wu, J-Y; Chang, C ...
Published in: PLoS One
November 17, 2009

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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.

Duke Scholars

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

November 17, 2009

Volume

4

Issue

11

Start / End Page

e7868

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Mutagenesis
  • Motor Skills
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Magnetic Resonance Imaging
  • Intracranial Pressure
  • Hydrocephalus, Normal Pressure
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lee, M.-J., Chang, C.-P., Lee, Y.-H., Wu, Y.-C., Tseng, H.-W., Tung, Y.-Y., … Chern, Y. (2009). Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus. PLoS One, 4(11), e7868. https://doi.org/10.1371/journal.pone.0007868
Lee, Ming-Jen, Ching-Pang Chang, Yi-Hsin Lee, Yi-Chih Wu, Hsu-Wen Tseng, Yu-Ying Tung, Min-Tzu Wu, et al. “Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus.PLoS One 4, no. 11 (November 17, 2009): e7868. https://doi.org/10.1371/journal.pone.0007868.
Lee M-J, Chang C-P, Lee Y-H, Wu Y-C, Tseng H-W, Tung Y-Y, et al. Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus. PLoS One. 2009 Nov 17;4(11):e7868.
Lee, Ming-Jen, et al. “Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus.PLoS One, vol. 4, no. 11, Nov. 2009, p. e7868. Pubmed, doi:10.1371/journal.pone.0007868.
Lee M-J, Chang C-P, Lee Y-H, Wu Y-C, Tseng H-W, Tung Y-Y, Wu M-T, Chen Y-H, Kuo L-T, Stephenson D, Hung S-I, Wu J-Y, Chang C, Chen Y-T, Chern Y. Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus. PLoS One. 2009 Nov 17;4(11):e7868.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

November 17, 2009

Volume

4

Issue

11

Start / End Page

e7868

Location

United States

Related Subject Headings

  • Polymorphism, Single Nucleotide
  • Mutagenesis
  • Motor Skills
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Magnetic Resonance Imaging
  • Intracranial Pressure
  • Hydrocephalus, Normal Pressure
  • Humans