Hydrocephalus is a disease that occurs sporadically in many mammalian species (1,2), but is relatively common in certain inbred strains of mice as a background characteristic. Although many people working with these strains are aware of it, little, if any information has been recorded or published.
Characteristics
Hydrocephalus is characterized by the presence of an abnormal amount of fluid in the cerebral ventricular system. In the laboratory mouse, at least 14 mutations have been described in which hydrocephalus is the primary defect or is part of the phenotype. These include "hydrocephalus-1" (hy-1), "hydrocephalus-2" (hy-2), "hydrocephalus-3" (hy-3), "brain-hernia" (bh), "cerebral degeneration" (cb), "congenital hydrocephalus" (ch), "dreher" (dr), "hydrocephalic-polydactyl" (hophpy), "hydrocephaly with the hop gait" (hyh), "obstructive hydrocephalus" (oh), "sightless" (Sig), "visceral inversion" (vi), and an unnamed mutation that occurs in Sums inbred strain (3). These mutations are usually recessive, as indicated by the lower case designation of the mutant gene symbol, sometimes with incomplete penetrance of hydrocephalus. Often the mutation has pleiotropic effects.
Causes
Hydrocephalus in mutant mice may be evident at birth or the animals may develop severe lesions and die between 20 and 40 days of age. Some live to sexual maturity, but die soon after (4,5). Apparent causes of hydrocephalus in mutant mice range from degenerative changes in the meninges (6) to occlusion of the aqueductal system (7).
Large production colonies of approximately 100 strains of inbred, congenic, F1 hybrid, or mutant laboratory mice are maintained at the Jackson Laboratory. Breeders are retired at between 5 and 10 months of age, depending upon the strain. One of the most common abnormalities submitted to the pathology lab for necropsy, has been diagnosed as internal hydrocephalus.
During a period of 12 months, from August 1, 1987 through July 31, 1988, data were collected from 512 pathology case reports maintained on a database (8). The diagnosis was made by gross examination of the brain at the time of necropsy.
Severely Affected Mice
The most severely affected mice had markedly domed skulls and ambulatory deficits to the point that they would just sit in one place in their cage . However, the majority had only slightly domed skulls at the time of presentation. Many mice were hyperactive as evidenced by a tendency to jump out of the transport cartons when the lids were removed. This is a characteristic that is atypical for the strains involved.
Reflection of the skin following euthanasia demonstrated thinned and deformed parietal bones . Sutures were open or closed, depending upon the severity of the ventricular dilation. The meninges were dark red, suggestive of either congestion or hemorrhage. The lateral ventricles were markedly enlarged and contained clear or red-tinged fluid. The cerebral cortex usually collapsed when the skull cap was removed, even when care was taken to prevent punctures or tears of the membrane-like structure that remained .
Coning of Midbrain
The lateral and third ventricles were markedly dilated in all cases examined . Various degrees of hemorrhage were evident in the meninges and in the ventricular spaces in the most severely affected cases. Hemosiderin-laden macrophages and/or fibrosis of the meninges indicated if these were subacute or chronic changes.
Coning of the midbrain was pronounced in all samples. The ependymal cells appeared to be morphologically normal in most cases. However, in several of the severely affected brains, ependymal cells lining the aqueducts were flattened.
The aqueduct of Sylvius appeared only mildly dilated when compared to normal brains, but it was abnormal in shape. At the narrowest region, normal aqueductal cross sections had a "T" shape, whereas those of hydrocephalic mice were slit-like, or, more rarely, triangular. The fourth ventricle appeared to be normal or slightly smaller than normal. No occlusions were found in the ventricular system of the tissues examined for the limited number of brains that were serially sectioned.
Internal Hydrocephalus
Internal hydrocephalus was diagnosed in 512 inbred mice representing 19 inbred strains and 4 F1 hybrid strains, during a 12 month period. This represented approximately 10% of all cases submitted to the diagnostic pathology laboratory. Nine strains and three F1 hybrids were diagnosed with hydrocephalus at a frequency of greater than 0.1% of the respective colonial population. Eleven of these were B10 congenic strains or the partner C57BL/10SnJ strain. The unrelated strain (BUB/BnJ) had only one case submitted and therefore was excluded from this high frequency grouping.
The age of the mice was known (±3 days) for 444 of the 512 cases (87%). Those cases for which the age was not known were excluded from further epidemiologic evaluation. The average age of presentation (AAP) for all hydrocephalic mice was found to be 44.3 ± 10.4 days, with a range of 6 to 100 days (Table 1). A one-way ANOVA test was applied to determine if there was a significant difference in the AAP between the B10 congenic and partner strains. A significant difference (p=0.0001) found between the inbred strains. Further comparison using the Scheffe F test showed that the C57BL/10SnJ strain had a significantly higher (p<0.05) AAP than did B10.AKM/SnJ (52.2 versus 36.3 days). No other significant differences were noted.
Table 1. Inbred Strains Diagnosed with Hydrocephalus in a 12 Month Study.
*Information based on 8 months of production.
Frequency in B10 Mice
The higher than background frequency among the related B10 congenic strains of mice suggested a genetic form of hydrocephalus. Unlike the single gene mutations with hydrocephalus as part of the phenotype that were described by Green (9), Clark (4,10), and Berry (6), hydrocephalus in these mice did not occur in a predictable Mendelian ratio. The higher frequency of occurrence in the B10 congenic and partner strains (0.12 to 0.86%), and the variability within these strains suggested that this was a multi-gene effect being concentrated in the B10 gene pool. Further evidence suggesting a multi-gene concentrating effect was a trend relating the AAP and the frequency of hydrocephalus. The age, at which mice were presented with clinical signs of hydrocephalus, although older than those reported for some congenital, inherited forms of the disease (3), would still suggest that this was a congenital condition. Further analysis of the genome of these mice may reveal specific genes or gene combinations that were responsible for the induction of hydrocephalus.
References
1. Szabo KT. Congenital Malformations in Laboratory and Farm Animals. Academic Press, Inc. San Diego, 1988.
2. Hochwald GM. Animal models of hydrocephalus: Recent developments. Proc Soc Exp Biol Med 1985; 178:1-11.
3. Lyon MF, Searle AG. Genetic Variants and Strains of the Laboratory Mouse. 2nd ed., Oxford Univ. Press, Oxford, 1989.
4. Clark FH. Two hereditary types of hydrocephalus in the house mouse (Mus musculus). Proc Natl Acad Sci 1935; 21:150-52.
5. Clark FH. Anatomical basis of hereditary hydrocephalus in the house mouse. Anat Rec 1934; 58:225-33.
6. Berry RJ. The inheritance and pathogenesis of hydrocephalus-3 in the mouse. J Pathol Bact 1961; 81:157-67.
7. McLone DG, Bondareff W, Raimondi AJ. Hydrocephalus-3, a murine mutant: II. Changes in the brain extracellular space. Surg Neurol 1973; 1:233-42.
8. Sundberg BA, Sundberg JP. A database system for small diagnostic pathology laboratories. Lab Anim (submitted for publication).
9. Green MC. The developmental effects of congenital hydrocephalus (ch) in the mouse. Develop Biol 1970; 23:585-608.
10 Clark FH. Hydrocephalus, a hereditary character in the house mouse. Proc Natl Acad Sci 1932; 18:654-56.
11. Richardson RR. Congenital genetic murine (ch) hydrocephalus. A structural model of cellular dysplasia and disorganization with the molecular locus of deficient proteoglycan synthesis. Child's Nerv Syst 1985; 1:87-99.