| First Author | Kotopoulis K | Year | 1996 |
| Journal | Mouse Genome | Volume | 94 |
| Issue | 1 | Pages | 146-8 |
| Mgi Jnum | J:32141 | Mgi Id | MGI:79645 |
| Citation | Kotopoulis K, et al. (1996) Seizures in a closed colony containing mice predominantly of C57BL/6J origin. Mouse Genome 94(1):146-8 |
| abstractText | Full text of Mouse Genome contribution: SEIZURES IN A CLOSED COLONY CONTAINING MICE PREDOMINANTLY OF C57BL/6J ORIGIN. Kristin Kotopoulis, Letitia Jordan, Sabine Kunig and Barbara B. Knowles. The Jackson Laboratory, Bar Harbor, Maine 04609. The genetic basis of seizures in mice is currently under active investigation. Seizure prone mouse mutants that result from a single gene defect have been identified (1, 2) and multigenic control of seizures has been documented in mice prone to audiogenic- and handling induced attacks (3, 4, 5). Based on our observation of mice in several different transgenic lineages, all derived from the C57BL/6J inbred strain, as well as of C57BL/6J mice themselves, we suggest that mice of this and possibly other inbred strains may have an innate tendency to develop seizures under certain conditions as they age. The observations for this study were all made in a closed animal colony. All of the mice housed in this room were either hysterectomy-derived or descended from hysterectomy-derived parents and have been raised in pathogen-free conditions. They are supplied with standard acidified water, fed NIH 31M rodent (6% fat content) diet, and are bedded in pine shavings. From 1 to 4 mice are housed in standard 5" high polycarbonate individually-vented cages in Thoren laminar flow cage racks. The room temperature is 65-75 degrees F, the humidity 40-60%, there are 9-15 air exchanges per hour and a 12 hour light/dark cycle is provided. The mice are changed in a laminar flow hood. Our initial observation was that several mice in this closed animal colony exhibited behavior which was consistent with a grand-mal type of epileptic seizure (6) at the time of their weekly cage change. These seizures can be characterized by the following set of guidelines. The first sign of seizure onset is a period of twitching and lurching forward. This is followed by a loss of postural control, tonic and clonic movements of the limbs and mild neck dorsoflexion. After a brief period, postural control is recovered, the tail becomes raised and stiff, and flexion of the neck occurs. This is then followed by hindleg clonus, and excessive salivation. The final stage of the attack involves chewing and grooming automatisms, such as repeated rubbing of the nose with both forearms, and general hyperactivity. At the conclusion of the seizure, the mouse lays on its side for a few seconds and then resumes normal activity. The entire event lasts approximately thirty seconds. There is most likely a refractory period associated with each seizure that must pass before another can occur. No adverse effects result from the seizure. The mouse can still mate and nurse pups properly, and no mortalities have been observed due to an attack. The original observations were made casually as the colony was not established for seizure research. However, we have since kept accurate records of 1,584 age-matched mice and have found a total of 45 that repeatedly developed obvious seizures during cage changing (Table 1). No difference between the number of males and females affected was found. Due to space limitations, an undetermined number of mice not exhibiting seizures were discarded, thus this figure should be regarded as a general estimate of the frequency of seizures in the population. Population*: Total Mice; Number of Seizure Mice: 45; Number of Total Mice: 1584; Percent: 2.84. Population*: C57BL/6J; Number of Seizure Mice: 18; Number of Total Mice: 869; Percent: 2.07. * Total includes both mice of the C57BL/6J strain and some induced mutants that contain an indeterminate proportion of the 129 ES cell genome. C57BL/6J are transgenic or normal mice from this inbred strain. Table 1. Seizures observed in transgenic, induced mutant and normal mice. Seizure phenotypes were detected in nine of the eighteen C57BL/6J-derived transgenic and induced mutant lineages, plus standard C57BL/6J mice housed in this room. In fact, two of the affected mice are C57BL/6J females purchased from The Jackson Laboratory and another was derived from a normal C57BL/6J x C57BL/6J-transgenic mating, but genotyped as negative for the transgene. Of the eighteen lineages observed, fourteen were either on a C57BL/6J background or had been backcrossed to C57BL/6J for over 20 generations. Four are insertional induced-mutations originating from 129-derived ES cells, backcrossed to C57BL/6J and are still segregating an indeterminate proportion of the 129 genome. Of the lineages that seize, five are transgenic for an alpha-amylase promoted-SV40 T antigen transgene and four are either induced mutant lineages or are derived by mating the SV40 T antigen transgenic and induced mutant mice (Figure 1). Some of the unaffected lineages are SV40 Tag transgenic and die from tumors at a relatively young age; these animals do not adequately represent non-seizure type mice because it is possible that they simply did not live long enough to develop seizures. Our observations of standard C57BL/6J animals are based on a small population kept in this room for breeding purposes. The large number of Beta2m+ that seize could contain more of the 129 genome than any of the other strains observed. Figure 1. (Legend). Number of mice with seizures in each lineage observed. The C57BL/6J lineages 324, 333/335, 334/354, 441 and 501 are SV40 T antigen-transgenic (7). The B2m+ strain is homozygous for an induced mutation in the Beta2, microglobulin gene and was derived from 129 ES cells; these mice were backcrossed to C57BL/6J and have been mated inter se (8). The CD4+ strain is homozygous for an induced mutation in the CD4 gene and was derived from a 129 ES cell; this founder mouse was backcrossed three times to C57BL/6J before mating inter se (9). The IL4+ lineage is homozygous for an induced mutation of the IL4 gene and was derived from 129 ES cells and it has been maintained by mating with C57BL/6J (10). The mean age at seizure onset is 10.9 months, with a range from 4.5 to 21 months of age (Figure 2). Once a mouse has exhibited an initial seizure at cage changing, it is seizure prone; on average a mouse that has previously seized will seize at 61% of its subsequent cage changes. It is possible that cage changing acts as a physical stimulus similar to the gentle tossing used to induce seizures in mice of the EL inbred strain (11). Figure 2. (Legend). Age at onset of seizures in mice from all strains affected (n=44). These seizures are likely attributable to factors other than the C57BL/6J genetic background. The B2m+ may contain a large proportion of the 129 genome. Although we did house BALB/c mice in the same room during this time and did not observe seizures, an equivalent number of aging mice was not observed. However, another investigator houses mice in this room and seizures were observed in his C.B-17 scid mice that are primarily of BALB/c origin. Environmental factors could play a role in the appearance of seizures, however, this has not been examined in a comparable closed mouse room. Our data suggests that seizures are relatively common in aging mice of the inbred strain C57BL/6J and this may hold true for other inbred strains as well. 1. Noebels JL, Qiao X, Bronson RT, Spencer C and Davisson MT. 1990. Epilepsy Research 7:129-135. 2. Toth M, Grimsby J, Buzsaki G and Donovan GP. 1995. Nature Genet 11:71-75. 3. Rise ML, Frankel WN, Coffin JM and Seyfried TN. 1991. Science 253:669-673. 4. Neumann PE and Collins RL. 1991. Proc Natl Acad Sci USA 88:5408-5412. 5. Frankel WN, Taylor BA, Noebels JL and Lutz CM. 1994. Genet 138:481-489. 6. The authors are grateful to Drs. Wayne Frankel and Jeff Noebels for confirming this diagnosis. 7. Fox N, Crooke R, Hwang LS, Schibler U, Knowles BB and Solter DS. 1989. Science 244:460-463. 8. Zijlstra M, Li E, Sajjadi F, Subramani S and Jaenisch R. 1989. Nature 342:435-438. 9. McCarrick JW, Parnes JR, Seong RH, Solter DS and Knowles BB. 1993. Transgenic Res 2:183-190. 10. Kopf M, Graham LG, Bachmann M, Lamers MC, Bluethmann H and Kohler G. 1993. Nature 362:245-248. 11. Imaizumi K, Ho S, Kutsokake G, Takizawa T, Fuziwara K et al. 1959. Exp Anim 8:6-10. |
