Morphological and Behavioral Changes in the Pathogenesis of a Novel Mouse Model of Communicating Hydrocephalus

Abstract

The Ro1 model of hydrocephalus represents an excellent model for studying the pathogenesis of hydrocephalus due to its complete penetrance and inducibility, enabling the investigation of the earliest cellular and histological changes in hydrocephalus prior to overt pathology. Hematoxylin and eosin staining, immunofluorescence and electron microscopy were used to characterize the histopathological events of hydrocephalus in this model. Additionally, a broad battery of behavioral tests was used to investigate behavioral changes in the Ro1 model of hydrocephalus. The earliest histological changes observed in this model were ventriculomegaly and disorganization of the ependymal lining of the aqueduct of Sylvius, which occurred concomitantly. Ventriculomegaly led to thinning of the ependyma, which was associated with periventricular edema and areas of the ventricular wall void of cilia and microvilli. Ependymal denudation was subsequent to severe ventriculomegaly, suggesting that it is an effect, rather than a cause, of hydrocephalus in the Ro1 model. Additionally, there was no closure of the aqueduct of Sylvius or any blockages within the ventricular system, even with severe ventriculomegaly, suggesting that the Ro1 model represents a model of communicating hydrocephalus. Interestingly, even with severe ventriculomegaly, there were no behavioral changes, suggesting that the brain is able to compensate for the structural changes that occur in the pathogenesis of hydrocephalus if the disorder progresses at a sufficiently slow rate.

MIM-Deficient Mice Exhibit Anatomical Changes in Dendritic Spines, Cortex Volume and Brain Ventricles, and Functional Changes in Motor Coordination and Learning

“…Learning defects and impaired motor coordination can be connected to the enlargement of ventricles (McMullen et al, 2012). The reason underlying ventricle enlargement is still unclear: the expression of MIM in the cells lining up the ventricle walls is modest or negligible (Figure 3C and data not shown), no differences were found in the ventricle cilia density and length (Figure 7), and analysis of the ventricle walls by electron microscopy did not show any obvious changes either (data not shown).…”

Dendritic and Synaptic Degeneration in Pyramidal Neurons of the Sensorimotor Cortex in Neonatal Mice With Kaolin-Induced Hydrocephalus

“…The possible cause of this difference may be due to the neglect of the hydrocephalic neonates by their mothers, neurogenic muscle atrophy, lethargy and general weakness of the hydrocephalic pups. Reduction in weight has been reported to be one of the first signs of development of hydrocephalus in experimental models (Del Bigio, 2001; López et al, 2003; McMullen et al, 2012; Johnston et al, 2013; Shaolin et al, 2015; Olopade et al, 2012). The body weight is an important index in developmental biology in neonatal pups and may be a pointer to an on-going pathologic condition.…”

Animal Models of Hydrocephalus

“…The hpy mice were also originally observed as offspring of X-irradiated mice [114] [116], but the specific factors associated with hydrocephalus development are unknown [117]. The unique double transgenic mouse model of communicating hydrocephalus shows severe ventricular enlargement and ependymal denudation and can be induced at any age because of doxycycline, which binds to tet-transactivator (tTA) and regulates astrocyte activation [118] [119]. It involves crossing of the G1-coupled Ro1 receptor activated solely by synthetic ligands (RASSL) in astrocytes mouse line with a tTA mouse line that has a fragment of human glial fibrillary acidic protein (GFAP) promoter that enables expression of Ro1 in astrocytes only.…”