EXPERIMENTAL
NEUROLOGY
47, 360-363 (1975)
RESEARCH Development
NOTE
of Audiogenic Seizure in Aged BALB/c Mice
G. RICHARD
GATES
AND CHIA-SRONG
Department of Psychology, Clayton, Victoria Received
Susceptibility
CHEN
Monash University, 3168, Australia
December 18, 1974
BALB/c mice are regarded as a strain resistant to audiogenic seizures becausethey do not usually show audiogenic seizure behavior on first exposure to a loud sound ( 1, 2). However, they can be primed for audiogenic seizure by exposure to a loud acoustic stimulus several days prior to testing (1, 2). In this report we present data which show that as BALB/c mice grow older, susceptibility to audiogenic seizure increases even though they have not been primed. This unexpected change in seizure susceptibility is consistent with the auditory deprivation hypothesis which has been put forward to explain induction of audiogenic seizure susceptibility (3, 8, 11, 17). Fifty-eight mice were separated as to sex shortly after weaning and were raised in the normal animal house environment until 342-366 days of age. They were then exposed to the sound of a 131 dB re. 0002 dyne/cm2 bell with the intention of priming them for 30 sec. On this first exposure to a loud sound, 12 out of 58 animals exhibited wild running, eight convulsed clonically, and one showed a tonic seizure (see Table 1). The percentage of wild running (21%) and clonic seizures (14%) shown by these unprimed animals was substantially higher than the almost zero incidence of seizure behavior shown by this same strain of mice in the 14-150 day old age range (1, 2, 7). In 20 mice aged 474-478 days, raised and tested under the same conditions as the 342-366 day old animals, 13 out of 20 exhibited wild running, and nine out of 20 showed clonic seizure. Again, there was a very large incidence of wild running (65%) and clonic seizure (45 % ) compared to younger unprimed animals. Moreover, a comparison between the 342-366 360 Copyright All rights
0 1975 by Academic Press, Inc. of reproduction in any form reserved.
361
SEIZURES TABLE SEIZURE
Age at test
SUSCEPTIBILITY IN UNPRIMED BALB/c 342-366 AND 474-478 DAYS OF AGE N
Wild running
58 20
12 13
(days) 342-366 474378
1
Clonic seizure 8 9
MICE
Tonic seizure 1 0
AT
Death
0 0
group and the 474-478 group shows that there are significant differences in incidence of wild running (x2 = 12.89, P < 0.001) and clonic seizure (x2 = 8.85, P < 0.01) with the older animals showing the higher rates. However, there were no significant differences between the groups in the latency to wild running or to clonic seizure (two-tailed Mann-Whitney U tests, U = 49.5 and 32.5, respectively, P’s > 0.05). The results of this experiment demonstrate that there is an increase in the rate of audiogenic seizure susceptibility as a function of age. Previously seizure-resistant mice become seizure-prone as they grow older. Recent evidence has shown that mice which are normally seizureresistant may become seizure-susceptible if their normal auditory input is reduced by a “deafening” priming exposure, destruction of the tympanic membrane, or by plugging the ear (3, 6, 8, 10, 11, 13). Reduction of input to higher auditory structures may cause them to become overreactive to the auditory stimulus which triggers the sequence of audiogenic seizure reactions shown during test (IS). S imilar physiological processes may be involved in the development of seizure susceptibility in these aged BALB/c mice. Rails (15, 16) has demonstrated that mice of the BALB/cJ strain show a substantial loss of high frequency sensitivity with age, even at 105-107 days of age. Thus it is likely that hearing loss, due to cochlear dysfunction, in aging mice is the factor responsible for our mice becoming susceptible to seizures without prior priming. It is possible that these mice might be “primed” by accidental noise not noticed by us in the animal room. However, the fact that there was no indication of any increase in seizure susceptibility in younger mice housed in the same room during this period seems to argue against this possibility. Postmortem examination of the tympanic membranes and middle ears of the mice revealed no signs of abnormality or infection as has been shown for audiogenic seizure-prone rats (5). Indeed the peripheral auditory structures presented a normal, healthy appearance further suggesting that the locus of dysfunction must be in the cochlear or auditory nerve.
362
FATES
AND
CHEN
It is conceivable that the constant noises of the animal house together with the effect of age have produced a hearing loss with time ‘comparable to the high frequency hearing loss or presbycusis shown in humans with advancing age (9, 12, 15, 19). Histological studies might clarify the type of hearing loss that has occurred. Regardless of the exact cause of the hearing loss which precipitates the development of the hypothesized supersensitive state, the present observation gives further support to our previous finding that susceptibility to seizures can be induced in fully mature BALB/c mice (7). The occurrence of seizure proneness with age raises an interesting question about the distinction which has been made between seizure-prone and seizure-resistant mice. Our results suggest that such a dichotomy is difficult to maintain as seizure-resistant mice became seizure-prone depending on age. Audiogenic seizure susceptibility might be better regarded as falling on an age continuum with those mice exhibiting seizure-proneness earliest also showing the earliest signs of cochlear dysfunction. Indeed, Ralls (15, 16) and others (4, 14) have shown that seizure-prone strains of mice exhibit auditory dysfunction at an early age. Furthermore, those mice with late audiogenic seizure susceptibility probably only reflect a late onset of cochlear dysfunction. In keeping with this notion it is interesting to find that seizure susceptible DBA mice show earlier signs of auditory dysfunction than the apparently seizure resistant BALB/c lines (15, 16). REFERENCES 1.
C. S. 1973. Sensitization for audiogenic seizures in two strains of mice and their F1 hybrids. Dev. Psychobiol. 6: 131-138. 2. CHEN, C. S. 1973.Effects of primingfor audiogenicseizuresin miceas a function of genotypeand soundintensity. J. Cow@. Physiol. Psychol. 84: 586-592. 3. CHEN, C. S., G. R. GATES, and G. R. BOCK.1973.Effect of priming and tympanicmembrane destructionon development and audiogenicseizuresusceptibility in BALB/c mice.Enp. Neural. 39 : 277-284. 4. DARROUZET, J., MARIE-M. NIAUSSAT, and A. GUILHAUME. 1967.A proposd’une absencede potentialmicrophonique:&de histologiquede l’organede corti de la souris.Rev. Laryrlgol. 11-12 : 813-833. 5. FLANDERA, V., V. Novkovb, and F. RECH. 1973.Role of infection in development of experimentalepilepticseizuresin rats. Physiol. Bohemoslov. 22: 209CHEN,
212.
J. L., and R. L. COLLINS. 1968.Temporalparametersof sensitizationfor audiogenicseizuresin SJL/J mice. Dcv. PsychobioZ. 1: M-188. 7. GATES, G. R., and C. S. CHEN. 1973.Priming for audiogenicseizuresin adult 6. FUI.LER,
BALB/c mice. Exfi. Neural. 41: 457-460. 8. GATES, G. R., C. S. CHEN, and G. R. BOCK. 1973. Effects of monaural and binaural auditory deprivation on audiogenic seizure susceptibility in BALB/c mice. Exp. Nrurol. 38 : 488-493. 9. HAWKINS, J. E. JR., 1973. Comparative otopathology : Aging, noise and ototoxic drugs. Adv. Oto-Rhino-Laryng. 20 : 125-141.
SEIZURES
363
10. HENRY, K. R. 1967. Audiogenic seizure susceptibility induced in C57BL/6J mice by prior auditory exposure. S&we 158: 938-940. 11. HENRY, K. R. 1973. Increased adult auditory responsiveness resulting from juvenile acoustic experience. Fed. Proc. 32 : 2098-2100. 12. HINCHCIJFFE, R. 1973. Epidemiology of sensorineural hearing loss. Audiology 12: 446-452. 13. MCGINN, M. D., J. F. WILLOTT, and K. R. HENRY. 1973. Effects of conductive hearing loss on auditory evoked potentials and audiogenic seizures in mice. Nature NC~LW Biol. 244 : 255-256. 14. NIAUSSAT, MARIE-M.. and J.-P. LECOUIX. 1967. Anomalies des responses microphoniques cochleaires dans une IignCe de souris presentant des crises convulsives au son. C. R. Acad. Sci. Paris 264: 103-105. 15. RALLS, K. S. 1965. Neurophysiological Studies of Hearing in Mice. Ph.D. thesis, Harvard University, Cambridge, Mass. 16. RALLS, K. S. 1967. Auditory sensitivity in mice. A&z. Bchav. 15 : 123-128. 17. SAUNDERS, J. C., G. R. BOCK, C. S. CHEN, and G. R. GATES. 1972. The effects of priming for audiogenic seizures on cochlear and behavioral responses in BALB/c mice. Exp. Neural. 36 : 426-436. 18. SAUNDERS, J. C., G. R. Bocx, R. JAEUCES, and C. S. CHEN. 1972. Effects of priming for audiogenic seizure on auditory evoked responses in the cochlear nucleus and inferior colliculus of BALB/c mice. Exp. Ncttrol. 37: 388394. 19. WEISS, A. D. 1959. Sensory Functions, pp. 503-542. 1st “Handbook of Aging and The Individual.” J. E. Birren [Ed.]. University of Chicago Press, Chicago, III.
NEUROLOGY
47, 360-363 (1975)
RESEARCH Development
NOTE
of Audiogenic Seizure in Aged BALB/c Mice
G. RICHARD
GATES
AND CHIA-SRONG
Department of Psychology, Clayton, Victoria Received
Susceptibility
CHEN
Monash University, 3168, Australia
December 18, 1974
BALB/c mice are regarded as a strain resistant to audiogenic seizures becausethey do not usually show audiogenic seizure behavior on first exposure to a loud sound ( 1, 2). However, they can be primed for audiogenic seizure by exposure to a loud acoustic stimulus several days prior to testing (1, 2). In this report we present data which show that as BALB/c mice grow older, susceptibility to audiogenic seizure increases even though they have not been primed. This unexpected change in seizure susceptibility is consistent with the auditory deprivation hypothesis which has been put forward to explain induction of audiogenic seizure susceptibility (3, 8, 11, 17). Fifty-eight mice were separated as to sex shortly after weaning and were raised in the normal animal house environment until 342-366 days of age. They were then exposed to the sound of a 131 dB re. 0002 dyne/cm2 bell with the intention of priming them for 30 sec. On this first exposure to a loud sound, 12 out of 58 animals exhibited wild running, eight convulsed clonically, and one showed a tonic seizure (see Table 1). The percentage of wild running (21%) and clonic seizures (14%) shown by these unprimed animals was substantially higher than the almost zero incidence of seizure behavior shown by this same strain of mice in the 14-150 day old age range (1, 2, 7). In 20 mice aged 474-478 days, raised and tested under the same conditions as the 342-366 day old animals, 13 out of 20 exhibited wild running, and nine out of 20 showed clonic seizure. Again, there was a very large incidence of wild running (65%) and clonic seizure (45 % ) compared to younger unprimed animals. Moreover, a comparison between the 342-366 360 Copyright All rights
0 1975 by Academic Press, Inc. of reproduction in any form reserved.
361
SEIZURES TABLE SEIZURE
Age at test
SUSCEPTIBILITY IN UNPRIMED BALB/c 342-366 AND 474-478 DAYS OF AGE N
Wild running
58 20
12 13
(days) 342-366 474378
1
Clonic seizure 8 9
MICE
Tonic seizure 1 0
AT
Death
0 0
group and the 474-478 group shows that there are significant differences in incidence of wild running (x2 = 12.89, P < 0.001) and clonic seizure (x2 = 8.85, P < 0.01) with the older animals showing the higher rates. However, there were no significant differences between the groups in the latency to wild running or to clonic seizure (two-tailed Mann-Whitney U tests, U = 49.5 and 32.5, respectively, P’s > 0.05). The results of this experiment demonstrate that there is an increase in the rate of audiogenic seizure susceptibility as a function of age. Previously seizure-resistant mice become seizure-prone as they grow older. Recent evidence has shown that mice which are normally seizureresistant may become seizure-susceptible if their normal auditory input is reduced by a “deafening” priming exposure, destruction of the tympanic membrane, or by plugging the ear (3, 6, 8, 10, 11, 13). Reduction of input to higher auditory structures may cause them to become overreactive to the auditory stimulus which triggers the sequence of audiogenic seizure reactions shown during test (IS). S imilar physiological processes may be involved in the development of seizure susceptibility in these aged BALB/c mice. Rails (15, 16) has demonstrated that mice of the BALB/cJ strain show a substantial loss of high frequency sensitivity with age, even at 105-107 days of age. Thus it is likely that hearing loss, due to cochlear dysfunction, in aging mice is the factor responsible for our mice becoming susceptible to seizures without prior priming. It is possible that these mice might be “primed” by accidental noise not noticed by us in the animal room. However, the fact that there was no indication of any increase in seizure susceptibility in younger mice housed in the same room during this period seems to argue against this possibility. Postmortem examination of the tympanic membranes and middle ears of the mice revealed no signs of abnormality or infection as has been shown for audiogenic seizure-prone rats (5). Indeed the peripheral auditory structures presented a normal, healthy appearance further suggesting that the locus of dysfunction must be in the cochlear or auditory nerve.
362
FATES
AND
CHEN
It is conceivable that the constant noises of the animal house together with the effect of age have produced a hearing loss with time ‘comparable to the high frequency hearing loss or presbycusis shown in humans with advancing age (9, 12, 15, 19). Histological studies might clarify the type of hearing loss that has occurred. Regardless of the exact cause of the hearing loss which precipitates the development of the hypothesized supersensitive state, the present observation gives further support to our previous finding that susceptibility to seizures can be induced in fully mature BALB/c mice (7). The occurrence of seizure proneness with age raises an interesting question about the distinction which has been made between seizure-prone and seizure-resistant mice. Our results suggest that such a dichotomy is difficult to maintain as seizure-resistant mice became seizure-prone depending on age. Audiogenic seizure susceptibility might be better regarded as falling on an age continuum with those mice exhibiting seizure-proneness earliest also showing the earliest signs of cochlear dysfunction. Indeed, Ralls (15, 16) and others (4, 14) have shown that seizure-prone strains of mice exhibit auditory dysfunction at an early age. Furthermore, those mice with late audiogenic seizure susceptibility probably only reflect a late onset of cochlear dysfunction. In keeping with this notion it is interesting to find that seizure susceptible DBA mice show earlier signs of auditory dysfunction than the apparently seizure resistant BALB/c lines (15, 16). REFERENCES 1.
C. S. 1973. Sensitization for audiogenic seizures in two strains of mice and their F1 hybrids. Dev. Psychobiol. 6: 131-138. 2. CHEN, C. S. 1973.Effects of primingfor audiogenicseizuresin miceas a function of genotypeand soundintensity. J. Cow@. Physiol. Psychol. 84: 586-592. 3. CHEN, C. S., G. R. GATES, and G. R. BOCK.1973.Effect of priming and tympanicmembrane destructionon development and audiogenicseizuresusceptibility in BALB/c mice.Enp. Neural. 39 : 277-284. 4. DARROUZET, J., MARIE-M. NIAUSSAT, and A. GUILHAUME. 1967.A proposd’une absencede potentialmicrophonique:&de histologiquede l’organede corti de la souris.Rev. Laryrlgol. 11-12 : 813-833. 5. FLANDERA, V., V. Novkovb, and F. RECH. 1973.Role of infection in development of experimentalepilepticseizuresin rats. Physiol. Bohemoslov. 22: 209CHEN,
212.
J. L., and R. L. COLLINS. 1968.Temporalparametersof sensitizationfor audiogenicseizuresin SJL/J mice. Dcv. PsychobioZ. 1: M-188. 7. GATES, G. R., and C. S. CHEN. 1973.Priming for audiogenicseizuresin adult 6. FUI.LER,
BALB/c mice. Exfi. Neural. 41: 457-460. 8. GATES, G. R., C. S. CHEN, and G. R. BOCK. 1973. Effects of monaural and binaural auditory deprivation on audiogenic seizure susceptibility in BALB/c mice. Exp. Nrurol. 38 : 488-493. 9. HAWKINS, J. E. JR., 1973. Comparative otopathology : Aging, noise and ototoxic drugs. Adv. Oto-Rhino-Laryng. 20 : 125-141.
SEIZURES
363
10. HENRY, K. R. 1967. Audiogenic seizure susceptibility induced in C57BL/6J mice by prior auditory exposure. S&we 158: 938-940. 11. HENRY, K. R. 1973. Increased adult auditory responsiveness resulting from juvenile acoustic experience. Fed. Proc. 32 : 2098-2100. 12. HINCHCIJFFE, R. 1973. Epidemiology of sensorineural hearing loss. Audiology 12: 446-452. 13. MCGINN, M. D., J. F. WILLOTT, and K. R. HENRY. 1973. Effects of conductive hearing loss on auditory evoked potentials and audiogenic seizures in mice. Nature NC~LW Biol. 244 : 255-256. 14. NIAUSSAT, MARIE-M.. and J.-P. LECOUIX. 1967. Anomalies des responses microphoniques cochleaires dans une IignCe de souris presentant des crises convulsives au son. C. R. Acad. Sci. Paris 264: 103-105. 15. RALLS, K. S. 1965. Neurophysiological Studies of Hearing in Mice. Ph.D. thesis, Harvard University, Cambridge, Mass. 16. RALLS, K. S. 1967. Auditory sensitivity in mice. A&z. Bchav. 15 : 123-128. 17. SAUNDERS, J. C., G. R. BOCK, C. S. CHEN, and G. R. GATES. 1972. The effects of priming for audiogenic seizures on cochlear and behavioral responses in BALB/c mice. Exp. Neural. 36 : 426-436. 18. SAUNDERS, J. C., G. R. Bocx, R. JAEUCES, and C. S. CHEN. 1972. Effects of priming for audiogenic seizure on auditory evoked responses in the cochlear nucleus and inferior colliculus of BALB/c mice. Exp. Ncttrol. 37: 388394. 19. WEISS, A. D. 1959. Sensory Functions, pp. 503-542. 1st “Handbook of Aging and The Individual.” J. E. Birren [Ed.]. University of Chicago Press, Chicago, III.
