Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus.
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.
Lee
Ming-Jen
MJ
Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chang
Ching-Pang
CP
Lee
Yi-Hsin
YH
Wu
Yi-Chih
YC
Tseng
Hsu-Wen
HW
Tung
Yu-Ying
YY
Wu
Min-Tzu
MT
Chen
Yen-Hui
YH
Kuo
Lu-Ting
LT
Stephenson
Dennis
D
Hung
Shuen-Iu
SI
Wu
Jer-Yuarn
JY
Chang
Chen
C
Chen
Yuan-Tsong
YT
Chern
Yijuang
Y
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
D005038:Ethylnitrosourea