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Auditory-evoked far-field potentials in myelin deficient mutant quaking mice
Neuroscience Vol. 5, PP. 2321 to 2323 Pergamon Press Ltd 1980. Prmted m Great Britain 0 IBRO
0306-4522/80:1201-2321802.00/0
AUDITORY-EVOKED MYELIN DEFICIENT
FAR-FIELD POTENTIALS IN MUTANT QUAKING MICE
S. N. SHAH and A. SALAMY University
of California, San Francisco, Langley Porter Institute, Brain-Behavior Sonoma State Hospital, Eldridge, California 95431, U.S.A.
Research
Center,
Abstract-Auditory evoked far-field potentials were recorded from mature quaking mice and their littermate controls. There was a significant prolongation in the latencies of all FFP peaks in the quaking mutants. Examination of the interaction between group (normal, quaking) and for selected pair-wise peak comparisons showed that the degree of retardation was not uniform for each FFP peak. In view of the reported histological and biochemical findings that the CNS of the quaking mutant is specifically deficient in myelin, we conclude that slowed conduction in the quaking mouse brain is due to myelin deficiency, and that non-uniform retardation of each FFP peak reflects regional variation in the extent of myelin deficiency. These data suggest that the changes in interpeak latencies of far-field potentials may be useful in identifying the demyelinated region(s) of the diseased central nervous system.
reliability of brainstem recordings of acoustically evoked responses has made this technique a useful clinical and research tool for studying disorders of the central nervous system (CNS). At a given stimulus intensity and rate of presentation the latencies of the complex auditory far-field potential (FFP) show a monotonic decline during maturation (JEWETT & ROMANO, 1972; SALAMY & MCKEAN, 1976; SHAH, BHARGAVA & MCKEAN, 1978b). In normal mature animals, however, this response is remarkably stable. The decrease in latency seen during brain development is believed to reflect primarily the functional state of myelination (SHAH et al., 1978b). Interference with myelin deposition during maturation (SHAH, BHARGAVA,JOHN~QN & MCKEAN, 1978a), disruption of myelin in adults (AMOCHAEV,JOHNSON, SALAMY& SHAH, 1979) through biochemical manipulations, demyelinating diseases such as multiple sclerosis (ROBINSON& RUDGE, 1977; STARR & ACHOR, 1975; STOCKARD & ROSSITTER, 1977), or normal aging (ROWE, 1978; ALLISON, GOFF & WOOD, 1979) results in the prolongation of all FFP latencies. Under such pathoanatomical conditions, however, a complexity of nervous system impairments may be involved. In this regard, various neurological mammalian mutants serve as valuable models for studying specific disorders of the CNS. The quaking and jimpy mice which show specific disturbance in myelin metabolism resulting in greatly diminished myelin in the brain (SIDMAN, DICKEI & APPEL, 1964) may constitute good models for studying the relationship between abnormalities in electrical activity of the nervous system and disorders of myelin. The life span of the jimpy mouse, however, is relatively short (about 20-30 days). In contrast, the quaking mouse, which represents an
THE
Abhreciations:
field potential; ance.
ANOVA, analysis of variance; FFP, farMANOVA, multivariate analysis of vari-
autosomal recessive neurological mutant, can easily be maintained and propagated in the laboratory. The name ‘quaking’ describes the outstanding clinical feature. When an affected animal is at rest and its trunk is in contact with bedding no abnormality is seen. When the bedding is cleared away the trunk begins to shake and as the mouse begins to explore, the amplitude of the tremor increases. The abnormal motor behavior is recognized at 10-12 days of postnatal age and reaches its full expression by about 3 weeks. In the present study we have examined the brainstem auditory FFP in quaking affected mice and their littermate controls in order to determine the specific relationship between changes in FFPs and myelin deficits.
EXPERIMENTAL
PROCEDURES
Auditory-evoked far field potentials were recorded in mature (45-80 days of age) quaking (affected mutants) and normal littermates. During the age period studied the myelin yield did not change (SINGH, SPRITZ & GEYER, 1971). The animals were anesthetized with a-chloralose (65 mg/kg,) and platinum needle electrodes (Grass EZ) were inserted subcutaneously at the vertex (active) of the scalp and referenced to the anterior pinna of the left ear. The animals were then placed in a small (8 x 13 x 13 in) electrically shielded box with a speaker (tweeter) positioned 10 in. directly above the surface of the head. The stimulus consisted of clicks (20~s duration) approximately 60dB (re: experimenters’ threshold) in intensity delivered at a rate of 15/s. Biopotentials were recorded with a Grass P511 preamplifier set to pass a signal between 30 Hz and 3 kHz (l/2 amplitude range). Fifteen huhdred (1500) FFPs were summated with a computer of average transients (Technical Measurements Corp. ClooO). Two-four averages were collected to ensure response reliability; however, latencies were measured on a single representative trace for each animal. The body temperature ranged between 32 and
2321
2322 2.5 r I ;; z 2.0 5
0
NORMAL
m
QUAKING
T
0
PEAKS Fig. 2. Mean & standard deviation of interpeak latcncies in sixteen quaking affected and sixteen littermntc control mice
Fig. I. Auditory evoked far-field potentials in quaking and littermate control mice. Typical X-Y plots of an average of 1500far-field potentials for (A) three littermate control and (B) three quaking mice.
(I-IV) are readily detectable in quaking mice, the latencies are clearly delayed. The mean values for each peak for sixteen experimental (quaking affected) and sixteen normal littermates are shown in Table 1. The results of the MANOVA revealed a strong main effect (groups), F = 168.33 (l/29), P <; 0.001 and a highly significant interaction term (groups x peaks}. F = 144.42 (3/87), P < 0.001. In addition the interpeak latency differences for all pair-wise comparisons assessed through a series of ANOVAS also exceeded
the 0.001 probability level (Fig. 2). DlSClJSSION
34’C at the time of recording. The average waveforms were written out with an X- Y plotter (Hewlett-Packard, 7004b) and the latencies of the first four (I-IV) positive peaks were determined. These data were then treated in a two-way multivariate analysis of variance (MANOVA) with repeated measures on one factor. All calculations were performed on the University’s IBM 370-48 computer. Interpeak latency differences were assessed through a series of univariate analyses of variance (ANQVA) on selected peak combinations (II-I. III--II and IVIII). RESULTS Figure 1 illustrates the striking differences in typical recording of FFPs from three normal and three quaking affected mice. Although the peaks of interest
Earlier
light- and electron-microscopic studies FRIEDE & REIMER. 1970; WISNEWSKI &
(SAMORAJSKI,
MORELL, 1971; WATANABE & BINGLE, 1972: BERGEN. 1971; FRIEDRICH, 1974) of quaking mouse brain have revealed the foBowing: (I ) the pathognomonic change in the brain of the quaking mouse is a dysfunction of the myelin forming system of both the ~r~pheral and central nervous system; (2) there was no impairment in the axonal growth; there was no evidence of infiltration or proliferation of macrophages; (3) gray matter showed no recognizable alterations of nerve cells or of synapses; (4) in the white matter the blood vessels appeared normal and there was no evidence of infiltration or proliferation of macrophages. Consistent with histological studies the biochemical analysis
TABLE 1. LATENCIES OF THE POSITIVEPEAKSOF BRAI~ST~~ AUDITORYEVOKH)POTWTIALS IN QUAKING ANDLIT~RMATE ~ONTRO~MI~ _~__._._-.__ -__. -__ --
Peak tatencies (ms) III
IV -___-_I 4.713 ) 0.333 3.893 k 0.286 2.140 k 0.135 3.167 + 0.244 Normal (16) 5.212 + 0.359* 7.100 f 0.459* Quaking (16) 2.606 + 0.235* 4.200 f 0.395* --._-_ -Each value is the mean + standard deviation. The numbers in parentheses represent the number of mice in each group * Significantly different from littermate controls (P < 0.001). I
II
Brainstem auditory potentials in myelin deficient mice of the mutant brain has shown that the change in lipid composition is compatible with a failure in the formation and maturation of myelin (HOGAN & JOSEPH, 1970). Furthermore, studies on brain myelin content by SINCH et al. (1971) have demonstrated that brains of quaking animals contained approximately one-fourth as much myelin as the littermate controls. Results of our present study show that quaking mutants displayed significantly longer latencies for all peaks of FFP, that is to say, slowed conduction was apparent at every level of brainstem auditory pathway from the 8th nerve to the inferior colliculi. In view of the reported histological and biochemical findings it is reasonable to conclude that the slow conduction or say the delayed latencies of the FFP in quaking mutants must directly result from the myelin deficiency. The significant difference in the interpeak latencies between the two groups indicate that the various peaks are not uniform in terms of the degree of retardation (see Fig. 2). This is consistent with the topographical studies of the quaking mouse nervous system (BERGER, 1971; FRIEDRICH, 1974; WISNIEWSKI
2323
& MORELL, 1971) showing that while the entire CNS shows incomplete myelinization, significant regional variation in the extent of myelin deficiency is apparent. The spinal cord, for example, is well myelinated with the degree of myelination decreasing rostrally. FAGG (1979) in his study on the regional content and composition of myelin found that the yield of myelin from various brain regions of affected animals ranged from 2:1’,of the control level in the most rostra1 parts of the CNS to 16% in the spinal cord, with an intermediate value of 10% for the optic nerve. Thus the non-uniformity in the degree of retardation of various FFP peaks (reflected in interpeak latency differences) may represent the variation in the extent of hypomyelination of the respective generator sources. The differential interaction effects of various peaks (pairwise comparisons) may therefore serve as a valuable tool in determining the regions affected in the diseased central nervous system. Acknowledgements-The authors are greatful for the technical assistance of Mr DOUGLAS MURRAY. This investigation was supported by grants from National Institutes of Health NS 14938 and NS 12424.
REFERENCES ALLISONT.,
GOFF W. R. & WORD C. C. (1979) Auditory, somatosensory and visual evoked potentials in the diagnosis of neuropathology: recording consideration and normative data. In Human Euoked Potentials (eds LEHMANN& CALLAWAY), pp. 1-16. Plenum Press, New York. AMOCHAEVA., JOHNSON R. C., SALAMY A. & SHAH S. N. (1979) Brainstem auditory evoked potentials and myelin changes in triethyltin-induced edema in young adult rats. Expl Neural. 66, 629-635. BERGERB. (1971) Quelques aspects ultrastructuraux de la substance blanche chez la souris quaking. Brain Res. 25,35-53. FAGG G. E. (1979) The quaking mouse: regional variations in the content and protein composition of myelin isolated from the central nervous system. Neuroscience 4, 973-987. FRIEDRICH,V. L., JR (1974) The myelin deficit in quaking mice. Brain Res. 82, 168-172. HCIGANE. L. & JOSEPHK. C. (1970) Composition of cerebral lipids in murine leucodystrophy: the quaking mutant. J. Neurochem. 17, 1209-1214. JEWETTD. L. & ROMANOM. N. (1972) Neonatal development of auditory system potentials averaged from the scalp of the rat and cat. Brain Rex 36, 101-115. ROBINSON K. & RUDGEP. (1977) Abnormalities of the auditory evoked potentials in patients with multiple sclerosis, Brain 11, 1940. ROWE M. J. (1978) Normal variability of the brainstem auditory evoked response in young and old adult subjects. Electroenceph. din. Neurophysiol. 44, 449470. SALAMYA. & MCKEAN C. M. (1976) Postnatal development of human brainstem potentials during the first year of life. Electroenceph. c/in. Neurophysiol. 40, 418426. SAMORAJSK~ T., FRIEDER. L. 8~ REIMERP. R. (1970) Hypomyelination in the quaking mouse: a model for the analysis of disturbed myelin formation. J. Neuropath. exp. Neural. 29, 507-523. SHAHS. N., BHARGAVA V. K., JOHNSONR. C. & MCKEAN C. M. (1978a) Latency changes in brainstem auditory evoked potentials associated with impaired brain myelination. Expl Neural. 58, 11l-1 18. SHAHS. N., BHARGAVA V. K. & MCKEAN C. M. (1978b) Maturational changes in early auditory evoked potentials and myelination of the inferior colliculus in rats. Neuroscience 3, 561-563. SIDMANR. L., DICKIE M. M. & APPEL S. H. (1964) Mutant mice (quaking and jimpy) with deficient myelination in the central nervous system. Science, N.Z 144, 309-311. SINGH H., SPRITZN. & GEYERB. (1971) Studies of brain myelin in the ‘quaking mouse’. J. Lipid Res. 12, 473481. STARRA. & ACHOR L. J. (1975) Auditory brainstem responses in neurological disease. Archs Neural. (Chicago) 32, 761-766. STOCKARDJ. J. & ROSSITTER V. S. (1977) Clinical and pathological correlates of brainstem auditory response abnormalities. Neurology, Minneap. 27, 316-325. WATANABEI. & BINGLEG. J. (1972) Dysmyelination in quaking mouse electron microscopic study. J. Neuropath exp. Neural. 31, 352-369.
WISN~EWSKI H. & MORELLP. (1971) Quaking mouse: ultrastructural evidence for arrest of myelinogenesis. Brain Res. 29, 63-73. (Accepted 13 June 1980)
0306-4522/80:1201-2321802.00/0
AUDITORY-EVOKED MYELIN DEFICIENT
FAR-FIELD POTENTIALS IN MUTANT QUAKING MICE
S. N. SHAH and A. SALAMY University
of California, San Francisco, Langley Porter Institute, Brain-Behavior Sonoma State Hospital, Eldridge, California 95431, U.S.A.
Research
Center,
Abstract-Auditory evoked far-field potentials were recorded from mature quaking mice and their littermate controls. There was a significant prolongation in the latencies of all FFP peaks in the quaking mutants. Examination of the interaction between group (normal, quaking) and for selected pair-wise peak comparisons showed that the degree of retardation was not uniform for each FFP peak. In view of the reported histological and biochemical findings that the CNS of the quaking mutant is specifically deficient in myelin, we conclude that slowed conduction in the quaking mouse brain is due to myelin deficiency, and that non-uniform retardation of each FFP peak reflects regional variation in the extent of myelin deficiency. These data suggest that the changes in interpeak latencies of far-field potentials may be useful in identifying the demyelinated region(s) of the diseased central nervous system.
reliability of brainstem recordings of acoustically evoked responses has made this technique a useful clinical and research tool for studying disorders of the central nervous system (CNS). At a given stimulus intensity and rate of presentation the latencies of the complex auditory far-field potential (FFP) show a monotonic decline during maturation (JEWETT & ROMANO, 1972; SALAMY & MCKEAN, 1976; SHAH, BHARGAVA & MCKEAN, 1978b). In normal mature animals, however, this response is remarkably stable. The decrease in latency seen during brain development is believed to reflect primarily the functional state of myelination (SHAH et al., 1978b). Interference with myelin deposition during maturation (SHAH, BHARGAVA,JOHN~QN & MCKEAN, 1978a), disruption of myelin in adults (AMOCHAEV,JOHNSON, SALAMY& SHAH, 1979) through biochemical manipulations, demyelinating diseases such as multiple sclerosis (ROBINSON& RUDGE, 1977; STARR & ACHOR, 1975; STOCKARD & ROSSITTER, 1977), or normal aging (ROWE, 1978; ALLISON, GOFF & WOOD, 1979) results in the prolongation of all FFP latencies. Under such pathoanatomical conditions, however, a complexity of nervous system impairments may be involved. In this regard, various neurological mammalian mutants serve as valuable models for studying specific disorders of the CNS. The quaking and jimpy mice which show specific disturbance in myelin metabolism resulting in greatly diminished myelin in the brain (SIDMAN, DICKEI & APPEL, 1964) may constitute good models for studying the relationship between abnormalities in electrical activity of the nervous system and disorders of myelin. The life span of the jimpy mouse, however, is relatively short (about 20-30 days). In contrast, the quaking mouse, which represents an
THE
Abhreciations:
field potential; ance.
ANOVA, analysis of variance; FFP, farMANOVA, multivariate analysis of vari-
autosomal recessive neurological mutant, can easily be maintained and propagated in the laboratory. The name ‘quaking’ describes the outstanding clinical feature. When an affected animal is at rest and its trunk is in contact with bedding no abnormality is seen. When the bedding is cleared away the trunk begins to shake and as the mouse begins to explore, the amplitude of the tremor increases. The abnormal motor behavior is recognized at 10-12 days of postnatal age and reaches its full expression by about 3 weeks. In the present study we have examined the brainstem auditory FFP in quaking affected mice and their littermate controls in order to determine the specific relationship between changes in FFPs and myelin deficits.
EXPERIMENTAL
PROCEDURES
Auditory-evoked far field potentials were recorded in mature (45-80 days of age) quaking (affected mutants) and normal littermates. During the age period studied the myelin yield did not change (SINGH, SPRITZ & GEYER, 1971). The animals were anesthetized with a-chloralose (65 mg/kg,) and platinum needle electrodes (Grass EZ) were inserted subcutaneously at the vertex (active) of the scalp and referenced to the anterior pinna of the left ear. The animals were then placed in a small (8 x 13 x 13 in) electrically shielded box with a speaker (tweeter) positioned 10 in. directly above the surface of the head. The stimulus consisted of clicks (20~s duration) approximately 60dB (re: experimenters’ threshold) in intensity delivered at a rate of 15/s. Biopotentials were recorded with a Grass P511 preamplifier set to pass a signal between 30 Hz and 3 kHz (l/2 amplitude range). Fifteen huhdred (1500) FFPs were summated with a computer of average transients (Technical Measurements Corp. ClooO). Two-four averages were collected to ensure response reliability; however, latencies were measured on a single representative trace for each animal. The body temperature ranged between 32 and
2321
2322 2.5 r I ;; z 2.0 5
0
NORMAL
m
QUAKING
T
0
PEAKS Fig. 2. Mean & standard deviation of interpeak latcncies in sixteen quaking affected and sixteen littermntc control mice
Fig. I. Auditory evoked far-field potentials in quaking and littermate control mice. Typical X-Y plots of an average of 1500far-field potentials for (A) three littermate control and (B) three quaking mice.
(I-IV) are readily detectable in quaking mice, the latencies are clearly delayed. The mean values for each peak for sixteen experimental (quaking affected) and sixteen normal littermates are shown in Table 1. The results of the MANOVA revealed a strong main effect (groups), F = 168.33 (l/29), P <; 0.001 and a highly significant interaction term (groups x peaks}. F = 144.42 (3/87), P < 0.001. In addition the interpeak latency differences for all pair-wise comparisons assessed through a series of ANOVAS also exceeded
the 0.001 probability level (Fig. 2). DlSClJSSION
34’C at the time of recording. The average waveforms were written out with an X- Y plotter (Hewlett-Packard, 7004b) and the latencies of the first four (I-IV) positive peaks were determined. These data were then treated in a two-way multivariate analysis of variance (MANOVA) with repeated measures on one factor. All calculations were performed on the University’s IBM 370-48 computer. Interpeak latency differences were assessed through a series of univariate analyses of variance (ANQVA) on selected peak combinations (II-I. III--II and IVIII). RESULTS Figure 1 illustrates the striking differences in typical recording of FFPs from three normal and three quaking affected mice. Although the peaks of interest
Earlier
light- and electron-microscopic studies FRIEDE & REIMER. 1970; WISNEWSKI &
(SAMORAJSKI,
MORELL, 1971; WATANABE & BINGLE, 1972: BERGEN. 1971; FRIEDRICH, 1974) of quaking mouse brain have revealed the foBowing: (I ) the pathognomonic change in the brain of the quaking mouse is a dysfunction of the myelin forming system of both the ~r~pheral and central nervous system; (2) there was no impairment in the axonal growth; there was no evidence of infiltration or proliferation of macrophages; (3) gray matter showed no recognizable alterations of nerve cells or of synapses; (4) in the white matter the blood vessels appeared normal and there was no evidence of infiltration or proliferation of macrophages. Consistent with histological studies the biochemical analysis
TABLE 1. LATENCIES OF THE POSITIVEPEAKSOF BRAI~ST~~ AUDITORYEVOKH)POTWTIALS IN QUAKING ANDLIT~RMATE ~ONTRO~MI~ _~__._._-.__ -__. -__ --
Peak tatencies (ms) III
IV -___-_I 4.713 ) 0.333 3.893 k 0.286 2.140 k 0.135 3.167 + 0.244 Normal (16) 5.212 + 0.359* 7.100 f 0.459* Quaking (16) 2.606 + 0.235* 4.200 f 0.395* --._-_ -Each value is the mean + standard deviation. The numbers in parentheses represent the number of mice in each group * Significantly different from littermate controls (P < 0.001). I
II
Brainstem auditory potentials in myelin deficient mice of the mutant brain has shown that the change in lipid composition is compatible with a failure in the formation and maturation of myelin (HOGAN & JOSEPH, 1970). Furthermore, studies on brain myelin content by SINCH et al. (1971) have demonstrated that brains of quaking animals contained approximately one-fourth as much myelin as the littermate controls. Results of our present study show that quaking mutants displayed significantly longer latencies for all peaks of FFP, that is to say, slowed conduction was apparent at every level of brainstem auditory pathway from the 8th nerve to the inferior colliculi. In view of the reported histological and biochemical findings it is reasonable to conclude that the slow conduction or say the delayed latencies of the FFP in quaking mutants must directly result from the myelin deficiency. The significant difference in the interpeak latencies between the two groups indicate that the various peaks are not uniform in terms of the degree of retardation (see Fig. 2). This is consistent with the topographical studies of the quaking mouse nervous system (BERGER, 1971; FRIEDRICH, 1974; WISNIEWSKI
2323
& MORELL, 1971) showing that while the entire CNS shows incomplete myelinization, significant regional variation in the extent of myelin deficiency is apparent. The spinal cord, for example, is well myelinated with the degree of myelination decreasing rostrally. FAGG (1979) in his study on the regional content and composition of myelin found that the yield of myelin from various brain regions of affected animals ranged from 2:1’,of the control level in the most rostra1 parts of the CNS to 16% in the spinal cord, with an intermediate value of 10% for the optic nerve. Thus the non-uniformity in the degree of retardation of various FFP peaks (reflected in interpeak latency differences) may represent the variation in the extent of hypomyelination of the respective generator sources. The differential interaction effects of various peaks (pairwise comparisons) may therefore serve as a valuable tool in determining the regions affected in the diseased central nervous system. Acknowledgements-The authors are greatful for the technical assistance of Mr DOUGLAS MURRAY. This investigation was supported by grants from National Institutes of Health NS 14938 and NS 12424.
REFERENCES ALLISONT.,
GOFF W. R. & WORD C. C. (1979) Auditory, somatosensory and visual evoked potentials in the diagnosis of neuropathology: recording consideration and normative data. In Human Euoked Potentials (eds LEHMANN& CALLAWAY), pp. 1-16. Plenum Press, New York. AMOCHAEVA., JOHNSON R. C., SALAMY A. & SHAH S. N. (1979) Brainstem auditory evoked potentials and myelin changes in triethyltin-induced edema in young adult rats. Expl Neural. 66, 629-635. BERGERB. (1971) Quelques aspects ultrastructuraux de la substance blanche chez la souris quaking. Brain Res. 25,35-53. FAGG G. E. (1979) The quaking mouse: regional variations in the content and protein composition of myelin isolated from the central nervous system. Neuroscience 4, 973-987. FRIEDRICH,V. L., JR (1974) The myelin deficit in quaking mice. Brain Res. 82, 168-172. HCIGANE. L. & JOSEPHK. C. (1970) Composition of cerebral lipids in murine leucodystrophy: the quaking mutant. J. Neurochem. 17, 1209-1214. JEWETTD. L. & ROMANOM. N. (1972) Neonatal development of auditory system potentials averaged from the scalp of the rat and cat. Brain Rex 36, 101-115. ROBINSON K. & RUDGEP. (1977) Abnormalities of the auditory evoked potentials in patients with multiple sclerosis, Brain 11, 1940. ROWE M. J. (1978) Normal variability of the brainstem auditory evoked response in young and old adult subjects. Electroenceph. din. Neurophysiol. 44, 449470. SALAMYA. & MCKEAN C. M. (1976) Postnatal development of human brainstem potentials during the first year of life. Electroenceph. c/in. Neurophysiol. 40, 418426. SAMORAJSK~ T., FRIEDER. L. 8~ REIMERP. R. (1970) Hypomyelination in the quaking mouse: a model for the analysis of disturbed myelin formation. J. Neuropath. exp. Neural. 29, 507-523. SHAHS. N., BHARGAVA V. K., JOHNSONR. C. & MCKEAN C. M. (1978a) Latency changes in brainstem auditory evoked potentials associated with impaired brain myelination. Expl Neural. 58, 11l-1 18. SHAHS. N., BHARGAVA V. K. & MCKEAN C. M. (1978b) Maturational changes in early auditory evoked potentials and myelination of the inferior colliculus in rats. Neuroscience 3, 561-563. SIDMANR. L., DICKIE M. M. & APPEL S. H. (1964) Mutant mice (quaking and jimpy) with deficient myelination in the central nervous system. Science, N.Z 144, 309-311. SINGH H., SPRITZN. & GEYERB. (1971) Studies of brain myelin in the ‘quaking mouse’. J. Lipid Res. 12, 473481. STARRA. & ACHOR L. J. (1975) Auditory brainstem responses in neurological disease. Archs Neural. (Chicago) 32, 761-766. STOCKARDJ. J. & ROSSITTER V. S. (1977) Clinical and pathological correlates of brainstem auditory response abnormalities. Neurology, Minneap. 27, 316-325. WATANABEI. & BINGLEG. J. (1972) Dysmyelination in quaking mouse electron microscopic study. J. Neuropath exp. Neural. 31, 352-369.
WISN~EWSKI H. & MORELLP. (1971) Quaking mouse: ultrastructural evidence for arrest of myelinogenesis. Brain Res. 29, 63-73. (Accepted 13 June 1980)