Hydrocephalus is a disorder that is defined by an accumulation of cerebrospinal fluid (CSF) in the ventricles of the brain. It is a rather common congenital condition, with an estimated incidence ranging between 0.4 and 0.8 per 1000 live births. Incidence varies significantly across different countries; it is almost two-fold higher in Africa compared to North America. Although hydrocephalus typically appears at birth or young infancy (77% of cases) it can manifest at any age (10% of cases in adults and 13% of cases in the elderly).
CSF is important for nourishing the cells of the central nervous system as it contains glucose and protein. It is produced by cells in the choroid plexus. The accumulation of CSF could arise from the overproduction of CSF, blockages in the ventricular system, or congenital structural deformations in the drainage system. Accumulation of CSF leads to increased pressure within the skull, which can have detrimental effects on the brain.
Depending on the site of blockage, there are two distinct types of hydrocephalus: communicating and non-communicating hydrocephalus. In the former, the flow of CSF is blocked outside of the ventricles, while in the latter, it is blocked within the ventricles. As mentioned previously, it is most common at birth or in early infancy (congenital hydrocephalus), but it may also occur later in life, usually as a result of a head injury or disease (acquired hydrocephalus).
Some potential causes of congenital hydrocephalus include complications during birth and infection during pregnancy, as this leads to swelling of the brain. The condition may also occur secondary to a physical defect in the development of the brain or spinal cord. Certain cases also appear to develop due to mutations in genes that are involved in CSF, although only a few such genes have been identified. One of these is L1CAM, an X-linked gene that encodes a cell adhesion molecule.
Diagnosis and Treatment
Congenital hydrocephalus may be noticed at birth if the baby’s head appears larger than usual. In this case, CT or MRI scans are performed to visualize the brain and ventricles. In fact, it is even possible to diagnose hydrocephalus in utero, preferably at 6 months of pregnancy when the ventricles are clearly formed. A non-invasive ultrasound can indicate whether there is fluid buildup in the ventricles.
In acquired hydrocephalus, CT or MRI scans are also used for diagnosis. They are performed if hydrocephalus is suspected, since individuals with acquired hydrocephalus exhibit overt symptoms similar to those seen in stroke patients, such as difficulty walking and talking.
Treatment of hydrocephalus involves surgery that will allow for the redirection of CSF into an alternative drainage route. This is known as a shunt treatment and the shunt typically remains implanted permanently. It consists of a collection catheter that is within the ventricles and an exit catheter that drains into another cavity, such as the abdomen.
Animal Models of Hydrocephalus
It is important to distinguish between models of acquired versus congenital hydrocephalus, since these vary in etiology and the presence of structural or genetic abnormalities. Some models are also designed to mimic either communicating or non-communicating hydrocephalus. This is a positive feature of hydrocephalus research, as the presence of a variety of specific models allows for more accurate analysis of each individual case or category of hydrocephalus. Most hydrocephalus models are genetic, while others are established by inbreeding rodents or introducing chemical or mechanical forms of obstruction.
One of the oldest models for congenital and non-communicating hydrocephalus is the hydrocephalus Texas rat (H-Tx) that was randomly created by breeding brothers and sisters of a strain of albino rats. The mechanisms underlying the induction of hydrocephalus in this model are poorly understood. Enlargements in the ventricular system can be detected as early as the fetal stages (in late gestation) and persists through the postnatal phase. Abnormalities can also be detected in the cerebral aqueduct that may partially explain the resulting obstruction. However, it has a low efficiency rate as it only develops in up to 40% of the rats. It is also challenging to study during the adult stages as these rats die at 4-6 weeks of age. Accordingly, this model is only suitable for the investigation of the pathophysiology that may drive congenital hydrocephalus in the fetus or newborn.
The Lew/Jms rat was created from an inbred strain of Wistar-Lewis rats. It is considered a model for congenital hydrocephalus as the fetuses show signs of hydrocephalus while in utero and are then born with hydrocephalus. They die shortly thereafter, within approximately 20 days. Similar to observations made in the H-Tx rat, Lew/Jms fetuses show occlusions in the cerebral aqueduct. The rat pups also had enlarged heads. Many of the pups exhibited severe hydrocephalus and were therefore euthanized to prevent further suffering. Interestingly, there were twice as many males as females, which may point towards the involvement of sex chromosomes.
The Hydrocephalus-3 (hy3) mouse model was discovered in the 1940s but the specific gene that caused the observed hydrocephalus was unknown. In the hy3 mouse, there does not appear to be obstruction between the ventricles; rather, there appears to be a defect in the reabsorption of CSF. Accordingly, it is a model for communicating hydrocephalus and can therefore help improve our understanding of factors that can influence or lead to reduced reabsorption and drainage of CSF from the ventricles. In fact, it was not until 60 years after the model was first established that researchers discovered a novel candidate gene that is disrupted in the hy3 model. The identified gene, Hydin, was shown to be expressed in the ependymal layer that lines the ventricles in brains of wild-type mice. The presence of this gene in the ependymal cells may be important for their function and this finding may point towards defects in ependymal cells, whose usual role is to produce CSF. However, some studies reported that changes in the ependymal layer are likely effects and not causes of hydrocephalus. Further investigation of the status of the ependymal layer is needed in order to gain more solid conclusions regarding their role in the pathology of the disease.
The hydrocephalus with hop gait (hyh) mouse model is a non-communicating hydrocephalus model that shows obstruction in the cerebral aqueduct. These mice resulted from a spontaneous autosomal mutation in a C57BL6/10J strain that led to hydrocephalus and lethality. It was later discovered that these mice harbor a point mutation in the gene encoding alpha-SNAP, an adaptor protein that is involved in many important processes, such as intracellular trafficking and synaptic protein recruitment. Like in the hy3 model, an eroded ependymal layer has been observed in the brains of hyh mice. This was seen before the onset of hydrocephalus, which points towards the possibility that this is a precipitating event in the development of hydrocephalus. Moreover, this degradation of the ependymal layer was followed by local activation of astrocyte proliferation and was associated with abnormalities in nearby brain structures, such as the corpus callosum. The discovery that the latter are effects that are secondary to ependymal layer degradation strengthens the idea that this may be a causative factor in the development of hydrocephalus.
The prh mutant mouse was established after the prh allele was identified as a driving factor in the development of early postnatal hydrocephalus in a genetic screen. These mice were later found to harbor a mutation in the Ccdc39 gene, which is important in motile cilia. Further studies on this model showed that there are significant defects in the cilia that are present on the choroid plexus and ependymal layer. Since the function of the cilia is thought to be critical for normal CSF circulation, any disruption in this (possibly through mutations in genes like Ccdc39) can lead to hydrocephalus.
Rsph9 Mutant Mouse
Similar to the prh model, the Rsph9 model is based on a deletion in another gene that is important in motile cilia since it encodes the radial spoke head protein (RSPH9) that forms part of the ciliary structure. Like prh mice, the Rsph9 mutant mice die shortly after birth. They also have abnormal ciliary motility in the ependymal layer and this was associated with its deterioration. Moreover, similar to what was seen in other studies, there was an increase in astrocyte proliferation, in addition to microglial activation. These models that are based on mutations in motile cilia genes are important for screening potential therapies that can rescue motile cilia function.
Models of Chemical Obstruction
In models of acquired hydrocephalus, various methods are used to induce CSF accumulation. The injection of kaolin, an aluminum silicate, into the ventricles has been shown to lead to non-communicating hydrocephalus and ventricular enlargement, mainly due to inflammation. Similarly, communicating acquired hydrocephalus has been induced by injecting kaolin into the subarachnoid matter or the basal cisterns. The kaolin injection model is one of the few models that are non-genetic in nature, and this may be an advantage since many cases of hydrocephalus do not seem to have genetic bases. Young injected with kaolin showed a quick reaction; they had much larger heads, altered body posture, and changes in gait (as observed in the open field test). However, they exhibited normal motor coordination and strength as compared to controls in the rotarod test.
Immunogenic injections with viruses or bacteria have also been shown to lead to communicating hydrocephalus, as they lead to inflammation and swelling of the brain, therefore resulting in hydrocephalus. Accordingly, it is suitable for modeling congenital or acquired hydrocephalus that is secondary to infection, because its immunogenicity limits its use in other cases of hydrocephalus as the role of the inflammation and immune system may confound the effects observed between other variables.
Models of Mechanical Obstruction
It should be noted that mechanical obstruction is also a possibility for the induction of hydrocephalus. Mechanical obstruction models require a surgery in which a plug made of cellophane or other materials is implanted in the ventricular system of the animal in order to lead to non-communicating hydrocephalus. Due to the difficulty of inserting an object into the ventricular system that has poor accessibility, this surgery may lead to secondary injuries in the brain tissue that could act as confounding factors. Accordingly, because of the small size of rodent brains, this procedure is typically avoided.
Hydrocephalus is a disease that imposes a major burden on society and a huge number of families every year. Although there are a wide variety of genetic and non-genetic rodent models available, many of the models were established randomly or by coincidence, which makes it challenging to identify the variables that are at play in each model. However, they have served as case studies in which specific questions, such as the role of certain genes or cell types, may affect or be affected by hydrocephalus. Studies on these models have yielded consistent information regarding the importance of the ependymal layer and motile cilia in the pathogenesis of hydrocephalus and the potential role of astrocytes. Our understanding of the causes of hydrocephalus and the development of alternative and novel treatments, or preventive procedures in the case of fetal hydrocephalus, are still lacking. Accordingly, extensive research is required on these different models.
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