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. METHODOLOGY/PRINCIPAL FINDINGS:Herein we report the characterization of a n...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-11-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2774278?pdf=render |
| _version_ | 1819263858133434368 |
|---|---|
| author | Ming-Jen Lee Ching-Pang Chang Yi-Hsin Lee Yi-Chih Wu Hsu-Wen Tseng Yu-Ying Tung Min-Tzu Wu Yen-Hui Chen Lu-Ting Kuo Dennis Stephenson Shuen-Iu Hung Jer-Yuarn Wu Chen Chang Yuan-Tsong Chen Yijuang Chern |
| author_facet | Ming-Jen Lee Ching-Pang Chang Yi-Hsin Lee Yi-Chih Wu Hsu-Wen Tseng Yu-Ying Tung Min-Tzu Wu Yen-Hui Chen Lu-Ting Kuo Dennis Stephenson Shuen-Iu Hung Jer-Yuarn Wu Chen Chang Yuan-Tsong Chen Yijuang Chern |
| author_sort | Ming-Jen Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T20:20:16Z |
| format | Article |
| id | doaj.art-0ffa8da6c72d4d118d450ac150f08ff3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T20:20:16Z |
| publishDate | 2009-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-0ffa8da6c72d4d118d450ac150f08ff32022-12-21T17:32:33ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-11-01411e786810.1371/journal.pone.0007868Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus.Ming-Jen LeeChing-Pang ChangYi-Hsin LeeYi-Chih WuHsu-Wen TsengYu-Ying TungMin-Tzu WuYen-Hui ChenLu-Ting KuoDennis StephensonShuen-Iu HungJer-Yuarn WuChen ChangYuan-Tsong ChenYijuang ChernBACKGROUND: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.http://europepmc.org/articles/PMC2774278?pdf=render |
| spellingShingle | Ming-Jen Lee Ching-Pang Chang Yi-Hsin Lee Yi-Chih Wu Hsu-Wen Tseng Yu-Ying Tung Min-Tzu Wu Yen-Hui Chen Lu-Ting Kuo Dennis Stephenson Shuen-Iu Hung Jer-Yuarn Wu Chen Chang Yuan-Tsong Chen Yijuang Chern Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus. PLoS ONE |
| title | Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus. |
| title_full | Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus. |
| title_fullStr | Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus. |
| title_full_unstemmed | Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus. |
| title_short | Longitudinal evaluation of an N-ethyl-N-nitrosourea-created murine model with normal pressure hydrocephalus. |
| title_sort | longitudinal evaluation of an n ethyl n nitrosourea created murine model with normal pressure hydrocephalus |
| url | http://europepmc.org/articles/PMC2774278?pdf=render |
| work_keys_str_mv | AT mingjenlee longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT chingpangchang longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT yihsinlee longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT yichihwu longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT hsuwentseng longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT yuyingtung longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT mintzuwu longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT yenhuichen longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT lutingkuo longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT dennisstephenson longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT shueniuhung longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT jeryuarnwu longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT chenchang longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT yuantsongchen longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus AT yijuangchern longitudinalevaluationofannethylnnitrosoureacreatedmurinemodelwithnormalpressurehydrocephalus |