Longitudinal Evaluation of an N-Ethyl-N-Nitrosourea-Created Murine Model with Normal Pressure Hydrocephalus

Abstract

BackgroundNormal-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 FindingsHerein 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/SignificanceOur 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.

Modulation of energy deficiency in Huntington's disease via activation of the peroxisome proliferator-activated receptor gamma

“…The gait of WT and R6/2 mice was assessed using a CatWalk gait automatic analyzer (Noldus Information Technology, Leesburg, VA, USA), as described elsewhere (77). The position, timing and dimensions of each footfall were recorded by a video camera positioned underneath a glass plate.…”

Validity and reliability of the CatWalk system as a static and dynamic gait analysis tool for the assessment of functional nerve recovery in small animal models

“…Recovery of function does not necessarily correlate with histological and electrophysiological evidence of regeneration (Munro, Szalai, Mackinnon, & Midha, 1998;Nichols et al, 2005;Valero-Cabré & Navarro, 2002). Nevertheless, functional analysis offers the most reliable way to demonstrate that a nerve has not only regenerated, but also made useful end organ connections (Lee et al, 2009).…”

Type VI adenylyl cyclase negatively regulates GluN2B-mediated LTD and spatial reversal learning

“…The brain structures of the mice were measured using micro-magnetic resonance imaging (MRI) analysis in the Taiwan Mouse Clinic and Transgenic Mouse Models Core (TMMC) as previously described 57 . Briefly, the mice were anesthetized using 2 ~ 3% isoflurane at a 1 L/min oxygenation rate.…”

“…To examine contextual and cued memory, the mice were placed in the fear-conditioning chamber (Med Associates, Saint Albans, VT, USA) and then received two pairs of conditioned stimuli (CS, white noise, 90 dB, 30 sec)-unconditioned stimuli (US, electric foot shock, 0.5 mA, 2 sec) in a 2-min interval as previously described 57 and detailed in the Supplementary Experimental Procedures. The freezing behavior of the mice during these tests was recorded and analyzed.…”