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Jaundiced Gunn rats have increased synaptic delays in the ventral cochlear nucleus
194
Brain Research, 501 (1989) 194-197 Elsevier
BRES 23786
Jaundiced Gunn rats have increased synaptic delays in the ventral cochlear nucleus Su Zhang, Robert E. Wickesberg and Donata Oertel Department of Neurophysiology, University of Wisconsin, Madison, WI 53706 (U.S.A.) (Accepted 18 July 1989)
Key words: Gunn rat; Bilirubin; Jaundice; Cochlear nucleus; Hearing
Recordings were made in vitro from cochlear nuclei of Gunn rats, a strain with a recessive mutation that predisposes rats to hyperbilirubinemia at birth. Delays between shocks to the auditory nerve and earliest synaptic responses of the cochlear nuclear neurons were on average longer in Gunn rats than in heterozygotes. Injections of sulfonamide further increased average synaptic delays in jaundiced rats. Responses to injected current in rats were like those in mice.
Bilirubin, a product of the catabolism of hemoglobin, is normally transported by serum albumin to the liver where it is conjugated with glucuronic acid and excreted into bile. Unconjugated bilirubin is diffusible and toxic to the central nervous system 9. Gunn 4'5 described a mutant strain of Wistar rats with a genetic predisposition to hyperbilirubinemia resuiting from an inability to conjugate bilirubin 2'4'7. The trait is transmitted as an autosomai recessive. Homozygous Gunn rats become yellow shortly after birth and at about 2 weeks of age show signs of neurological dysfunction. Waves II and III of evoked responses to clicks, probably associated with responses in the brainstem auditory nuclei, are abnormally small and have abnormally long latencies 17' ~s.~9 Treatment of Gunn rats with sulfa drugs exacerbates the pathological disorders 15"16, presumably by displacing bilirubin from albumin and promoting a net transfer of bilirubin to the brain 9. To understand the effects of hyperbilirubinemia on the cochlear nuclei, intracellular recordings were made from slices. Slices were prepared and maintained as described previously for mice 1°'11. Rats, 15-21 days old, were
obtained from a colony at the University of Wisconsin Waisman Center, in which homozygous, jaundiced males (/j) were mated with heterozygous, unjaundiced females (Jj). Four groups of animals were studied: (1) untreated jaundiced, Gunn rats Qj), (2) phenotypically normal heterozygotes (Jj), and (3) homozygous (/~/+s) and (4) heterozygous Gunn rats (Jj+s) injected subcutaneously with sulfadimethoxine (Hoffmann-La Roche Inc.) 100-200 mg/kg, 45 min to 2 days prior to the experiment. In rats, as in mice 12'22, neurons of the cochlear nuclei have electrical properties of one of three types (Fig. 1A-C). Cells in the ventral cochlear nucleus (VCN) which fire large action potentials regularly (Fig. 1A) have been associated with stellate cells in mice 22. Others that fire only one or two small action potentials and show strong rectification in the physiological voltage range (Fig. IB), have been recorded from bushy cells in mice 2e. In the dorsal cochlear nucleus (DCN) cells fire large action potentials that are followed by double undershoots in rats (Fig. 1C) as in mice 12. Stimulation of the auditory nerve evokes excitatory postsynaptic potentials (EPSPs) in neurons of
Correspondence: S. Zhang, Department of Neurophysiology, 281 Medical Sciences Building, University of Wisconsin-Madison, Madison, WI 53706, U.S.A. OOO6-ROO~IR9150~.SOt~ 1989 Elsevier Science Publishers B.V. (Biomedical Division)
195
A
B
C
+0.5 nA
-55
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-85["
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I
o
~
i
,
,
i
+1.4 nA
"
30 msec
E
F
E -62 L
60V
I 0
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I
D -45
+0.7 nA
!
I 5 msec I 0
I 5 rnsec
I 0
I 5 rnsec
Fig. 1. Intracellular recordings from the cochlear nuclei of rats. A-C: upper panels show the membrane potential changes resulting from injection of current pulses whose amplitude is indicated. Three types of intrinsic electrical properties are revealed in records from 3 cells from a rat that was 15 days old. In mice the same three cell types have been identified with intraceilular injections of horseradish peroxidase as being recorded from stellate (A) 36, bushy (B) 36 and cells of the DCN (C) 23. D-F: lower panels show synaptic responses to electrical stimulation of the auditory nerve (arrows). D: synaptic responses from normal rat, same cell as B. E,F: records from 2 cells in jaundiced rat, 20 days old.
the V C N of rats (Fig. 1 D - F ) , as of mice 1°. Responses to shocks that are just over threshold can have relatively long and variable delays. A s the shock strength is increased, the latency reaches a m i n i m u m , staying constant over large ranges in shock strength 1°'11'23. T h e delays b e t w e e n shocks to the auditory nerve and the EPSPs in the V C N indicate that responses are m o n o s y n a p t i c and thus are likely to r e p r e s e n t excitation of postsynaptic cells by a u d i t o r y nerve fibers 1°. T h e shortest delays b e t w e e n the beginning of shocks (0.1 ms duration) to the auditory nerve and the earliest rise of the E P S P from the baseline were m e a s u r e d in 110 cells in 16 slices. M e a s u r e m e n t s were m a d e from four groups of animals: 30 recordings from 4 u n j a u n d i c e d heterozygous controls (Jj), 26 recordings from 3 heterozygotes with sulfa injections (Jj + s), 24 recordings from 4 jaundiced h o m o z y g o t e s (/j), and 30 recordings from 5 jaundiced h o m o z y g o t e s with sulfa injections Qj + s). Synaptic delays were on average longer in jaundiced" animals than in n o r m a l ones. In j a u n d i c e d G u n n rats the EPSPs in m a n y neurons had m i n i m u m latencies
within the n o r m a l range but others were a b n o r m a l l y long (Fig. 1E,F). Differences in delays were not the result of differences in threshold. S o m e t i m e s synaptic delays s h o r t e n e d with increasing stimulus strength, especially n e a r threshold. F o r e x a m p l e , the
TABLE I
Mean minimal synaptic delays Mean minimal synaptic delays + S.D. (ms) recorded from jaundiced and unjaundiced animals with and without sulfa treatment. The number of cells (c), number of slices (s) and average age of cell in days (d) in each of the 4 animal groups are also given. Differences were assessed with two-tailed t-tests.
Unjaundiced (J]) Jaundiced (3)') Latency difference
Without sulfa
With sulfa
Latency diff.
0.80 + 0.16 30c, 4s, 18d 0.98 + 0.35 24c, 4s, 21d 0.18"
0.84 + 0.13 26c, 3s, 18d 1.15 + 0.23 30c, 5s, 18d 0.31"*
0.04
*P < 0.05, **P < 0.01; significantly different.
0.17"
196 EPSPs illustrated in Fig. 1E have longer delays after a 6 V shock than after a 20 V shock. Measurements were therefore made over a wide range of stimulating voltages in order to obtain a reliable minimum latency. Administration of sulfonamide increased synaptic delays in jaundiced rats further. Two-tailed t-tests, with correction for unequal variance, were used to determine the significance of the differences in synaptic delays among animal groups. The means of 4 groups of VCN neurons' minimum synaptic delays are compared in Table I. Mean minimal synaptic delays systematically increase with expected free bilirubin. Sulfa injections in the unjaundiced rats did not change minimal synaptic delays. The mean minimal latency in homozygotes was significantly higher than that of heterozygous controls. Sulfa injections in homozygotes increased the mean minimal latency further. The increase in latency in jaundiced Gunn rats is not likely to arise from a decreased conduction velocity. At about 10 m/s TM, it takes 0.02 ms for action potentials to be propagated from the stimulating electrodes to the terminals in the VCN (200 Hm). To account for a difference of 1.0 ms between normal and severely abnormal latencies, the conduction velocity would have to decrease from about 10 to 0.2 m/s. Such slow conduction is not known in myelinated fibers14; conduction would probably be blocked under such circumstances '3. Furthermore, anatomical studies give no indication of abnormalities in auditory nerve fibers that could account for such drastic reduction in the conduction velocity 1. More probably, the increase in latency arises from a slowing in the presynaptic events. The monosynaptic EPSPs are the result of the activation of kainate receptors 21, which are unlikely to be associated with a second-messenger system 8. If bilirubin were to interfere with postsynaptic receptors, rise times, not latencies, of EPSPs would be altered. It seems likely, therefore, that the lengthening of transmission from 0.7 to 2.0 ms in jaundiced rats results from changes in presynaptic events. In cells with EPSPs whose minimum latencies were abnormally long, all detected, converging EPSPs must have had to be delayed. Minimum latencies represent responses to shocks which are well above threshold and in most, if not all, cases
represent responses to several converging auditory nerve fibers 11. Bilirubin could interfere with the release of neurotransmitter by making complexes with phospholipids at the presynaptic terminals 3'2°. Bilirubin binds sphingomyelin and pure gangliosides with an affinity 5-25 times higher than other lipids 2°. These lipids are particularly abundant in the outer leaflet of the synaptosomal membrane. Furthermore, bilirubin binds synaptosomes from young animals more effectively than those from mature animals, especially at slightly acid pH 2°. The Gunn rats were chosen at ages between 2 and 3 weeks when the homozygotes O)') have the greatest bilirubin level of 12-16 mg/dl in serum 6. The latencies of synaptic responses to the auditory inputs in the murine VCN are longer and more variable before the age of 12 days 23. It is possible that elevated levels of bilirubin retard the neural development of some cells in homozygous Gunn rats, resulting in longer latencies than in heterozygous littermates of comparable ages. The present results are consistent with measurements of brainstem evoked responses to click stimuli in vivo. Shapiro and H e c o x 18'19 have shown that average brainstem responses from homozygous animals had increased wave I - I I intervals, reduced wave II and 1II amplitudes, and abnormal wave morphology in comparison with those in normal littermates. If wave I represents the invasion of the cochlear nuclei by activity in auditory nerve fibers and wave II represents activity in the cochlear nucleus, the lengthening of the interval between them in the jaundiced Gunn rat is what would be expected if synaptic delays are abnormally long. Furthermore, wave II is often split as if two populations of neurons respond at two different times, the latency of the response in one of the populations being normal and the other abnormally long. Also consistent with the present results is that in jaundiced Gunn rats intervals between waves II and III, I and II, and I and III increased two hours after sulfonamide injections 17. We thank Drs. Brugge, Shapiro, Odell and WhitIon for helpful suggestions and criticisms. The work was supported by N I H grants 17590 and 12732.
197 1 Brugge, J.F., Shapiro, S.M. and Smith, P.H., Conditions of the cochlear nuclei of the hyperbilirubinemic Gunn rat, Ass. Res. Otolaryngol. Abstr., (1987) 97-98. 2 Carbone, J.V. and Grodsky, G.M., Constitutional nonhemolytic hyperbilirubinemia in the rat: defect of bilirubin conjugation, Proc. Soc. Exp. Biol. Med., 94 (1957) 461-463. 3 Eriksen, E., Danielsen, H. and Brodersen, R., Bilirubinliposome interaction, J. Biol. Chem., 256 (1981) 42694274. 4 Gunn, C.K., Hereditary acholuric jaundice, J. Hered., 29 (1938) 137-139. 5 Gunn, C.K., Hereditary acholuric jaundice in the rat, Can. Med. Assoc. J., 50 (1944) 230-237. 6 Johnson, L., Sarmiento, F., Blanc, W.A. and Day, R., Kernicterus in rats with an inherited deficiency of glucuronyl transferase, Am. J. Dis. Child., 97 (1959) 591-608. 7 Lathe, G.H. and Walker, M., The synthesis of bilirubin glucuronide in animal and human liver, Biochem. J., 70 (1958) 705-712. 8 Mayer, M.L. and Westbrook, G.L., The physiology of excitatory amino acids in the vertebrate central nervous system, Prog. Neurobiol., 28 (1987) 197-276. 9 Odell, G.B., The dissociation of bilirubin from albumin and its clinical implications, J. Pediatr., 55 (1959) 268-279. 10 Oertel, D., Synaptic responses and electrical properties of cells in brain slices of the mouse anteroventral cochlear nucleus, J. Neurosci., 3 (1983) 2043-2053. 11 Oertel, D., Use of brain slices in the study of the auditory system: spatial and temporal summation of synaptic inputs in cells in the anteroventral cochlear nucleus of the mouse, J. Acoust. Soc. Am., 78 (1985) 328-333. 12 Oertel, D. and Wu, S.H., Morphology and physiology of cells in slice preparations of the dorsal cochlear nucleus of mice, J. Comp. Neurol., 283 (1989) 228-247.
13 Ramon, F., Joyner, R.W. and Moore, J.W., Propagation of action potentials in inhomogeneous axon regions, Fed. Proc., 34 (1975) 1357-1363. 14 Ritchie, J.M., On the relation between fibre diameter and conduction velocity in myelinated nerve fibers, Proc. R. Soc. Lond. B, 217 (1982) 29-35. 15 Rose, A.L. and Wisniewski, 'H., Acute bilirubin encephalopathy induced with sulfadimethoxine in Gunn rats, J. Neuropathol. Exp. Neurol., 38 (1979) 152-164. 16 Schutta, H.S. and Johnson, L., Clinical signs and morphologic abnormalities in Gunn rats treated with sulfadimethoxine, J. Pediatr., 75 (1969) 1070-1079. 17 Shapiro, S.M., Acute brainstem auditory evoked potential abnormalities in jaundiced Gunn rats given sulfonamide, Pediatr. Res., in press. 18 Shapiro, S.M. and Hecox, K.E., Brainstem auditory evoked potentials in jaundiced Gunn rats, Ann. Otol. RhinoL Laryngol., in press. 19 Shapiro, S.M. and Hecox, K.E., Development of brainstem auditory evoked potentials in heterozygous and homozygous jaundiced Gunn rats, Dev. Brain Res., 41 (1988) 147-157. 20 Vazquez, J., Garcia-Calvo, M., Valdivieso, F., Mayor, F. and Mayor, F. Jr., Interaction of bilirubin with the synaptosomal plasma membrane, J. Biol. Chem., 263 (1988) 1255-1265. 21 Wickesberg, R.E. and Oertel, D., Auditory nerve neurotransmitter acts on a kainate receptor, Brain Research, 486 (1989) 39-48. 22 Wu, S.H. and Oertel, D., Intracellular injection with horseradish peroxidase of physiologically characterized stellate and bushy cells in slices of mouse anteroventral cochlear nucleus, J. Neurosci., 4 (1984) 1577-1588. 23 Wu, S.H. and Oertel, D., Maturation of synapses and electrical properties, Hearing Res., 30 (1987) 99-110.
Brain Research, 501 (1989) 194-197 Elsevier
BRES 23786
Jaundiced Gunn rats have increased synaptic delays in the ventral cochlear nucleus Su Zhang, Robert E. Wickesberg and Donata Oertel Department of Neurophysiology, University of Wisconsin, Madison, WI 53706 (U.S.A.) (Accepted 18 July 1989)
Key words: Gunn rat; Bilirubin; Jaundice; Cochlear nucleus; Hearing
Recordings were made in vitro from cochlear nuclei of Gunn rats, a strain with a recessive mutation that predisposes rats to hyperbilirubinemia at birth. Delays between shocks to the auditory nerve and earliest synaptic responses of the cochlear nuclear neurons were on average longer in Gunn rats than in heterozygotes. Injections of sulfonamide further increased average synaptic delays in jaundiced rats. Responses to injected current in rats were like those in mice.
Bilirubin, a product of the catabolism of hemoglobin, is normally transported by serum albumin to the liver where it is conjugated with glucuronic acid and excreted into bile. Unconjugated bilirubin is diffusible and toxic to the central nervous system 9. Gunn 4'5 described a mutant strain of Wistar rats with a genetic predisposition to hyperbilirubinemia resuiting from an inability to conjugate bilirubin 2'4'7. The trait is transmitted as an autosomai recessive. Homozygous Gunn rats become yellow shortly after birth and at about 2 weeks of age show signs of neurological dysfunction. Waves II and III of evoked responses to clicks, probably associated with responses in the brainstem auditory nuclei, are abnormally small and have abnormally long latencies 17' ~s.~9 Treatment of Gunn rats with sulfa drugs exacerbates the pathological disorders 15"16, presumably by displacing bilirubin from albumin and promoting a net transfer of bilirubin to the brain 9. To understand the effects of hyperbilirubinemia on the cochlear nuclei, intracellular recordings were made from slices. Slices were prepared and maintained as described previously for mice 1°'11. Rats, 15-21 days old, were
obtained from a colony at the University of Wisconsin Waisman Center, in which homozygous, jaundiced males (/j) were mated with heterozygous, unjaundiced females (Jj). Four groups of animals were studied: (1) untreated jaundiced, Gunn rats Qj), (2) phenotypically normal heterozygotes (Jj), and (3) homozygous (/~/+s) and (4) heterozygous Gunn rats (Jj+s) injected subcutaneously with sulfadimethoxine (Hoffmann-La Roche Inc.) 100-200 mg/kg, 45 min to 2 days prior to the experiment. In rats, as in mice 12'22, neurons of the cochlear nuclei have electrical properties of one of three types (Fig. 1A-C). Cells in the ventral cochlear nucleus (VCN) which fire large action potentials regularly (Fig. 1A) have been associated with stellate cells in mice 22. Others that fire only one or two small action potentials and show strong rectification in the physiological voltage range (Fig. IB), have been recorded from bushy cells in mice 2e. In the dorsal cochlear nucleus (DCN) cells fire large action potentials that are followed by double undershoots in rats (Fig. 1C) as in mice 12. Stimulation of the auditory nerve evokes excitatory postsynaptic potentials (EPSPs) in neurons of
Correspondence: S. Zhang, Department of Neurophysiology, 281 Medical Sciences Building, University of Wisconsin-Madison, Madison, WI 53706, U.S.A. OOO6-ROO~IR9150~.SOt~ 1989 Elsevier Science Publishers B.V. (Biomedical Division)
195
A
B
C
+0.5 nA
-55
I
-85["
r
I
o
~
i
,
,
i
+1.4 nA
"
30 msec
E
F
E -62 L
60V
I 0
l
I
D -45
+0.7 nA
!
I 5 msec I 0
I 5 rnsec
I 0
I 5 rnsec
Fig. 1. Intracellular recordings from the cochlear nuclei of rats. A-C: upper panels show the membrane potential changes resulting from injection of current pulses whose amplitude is indicated. Three types of intrinsic electrical properties are revealed in records from 3 cells from a rat that was 15 days old. In mice the same three cell types have been identified with intraceilular injections of horseradish peroxidase as being recorded from stellate (A) 36, bushy (B) 36 and cells of the DCN (C) 23. D-F: lower panels show synaptic responses to electrical stimulation of the auditory nerve (arrows). D: synaptic responses from normal rat, same cell as B. E,F: records from 2 cells in jaundiced rat, 20 days old.
the V C N of rats (Fig. 1 D - F ) , as of mice 1°. Responses to shocks that are just over threshold can have relatively long and variable delays. A s the shock strength is increased, the latency reaches a m i n i m u m , staying constant over large ranges in shock strength 1°'11'23. T h e delays b e t w e e n shocks to the auditory nerve and the EPSPs in the V C N indicate that responses are m o n o s y n a p t i c and thus are likely to r e p r e s e n t excitation of postsynaptic cells by a u d i t o r y nerve fibers 1°. T h e shortest delays b e t w e e n the beginning of shocks (0.1 ms duration) to the auditory nerve and the earliest rise of the E P S P from the baseline were m e a s u r e d in 110 cells in 16 slices. M e a s u r e m e n t s were m a d e from four groups of animals: 30 recordings from 4 u n j a u n d i c e d heterozygous controls (Jj), 26 recordings from 3 heterozygotes with sulfa injections (Jj + s), 24 recordings from 4 jaundiced h o m o z y g o t e s (/j), and 30 recordings from 5 jaundiced h o m o z y g o t e s with sulfa injections Qj + s). Synaptic delays were on average longer in jaundiced" animals than in n o r m a l ones. In j a u n d i c e d G u n n rats the EPSPs in m a n y neurons had m i n i m u m latencies
within the n o r m a l range but others were a b n o r m a l l y long (Fig. 1E,F). Differences in delays were not the result of differences in threshold. S o m e t i m e s synaptic delays s h o r t e n e d with increasing stimulus strength, especially n e a r threshold. F o r e x a m p l e , the
TABLE I
Mean minimal synaptic delays Mean minimal synaptic delays + S.D. (ms) recorded from jaundiced and unjaundiced animals with and without sulfa treatment. The number of cells (c), number of slices (s) and average age of cell in days (d) in each of the 4 animal groups are also given. Differences were assessed with two-tailed t-tests.
Unjaundiced (J]) Jaundiced (3)') Latency difference
Without sulfa
With sulfa
Latency diff.
0.80 + 0.16 30c, 4s, 18d 0.98 + 0.35 24c, 4s, 21d 0.18"
0.84 + 0.13 26c, 3s, 18d 1.15 + 0.23 30c, 5s, 18d 0.31"*
0.04
*P < 0.05, **P < 0.01; significantly different.
0.17"
196 EPSPs illustrated in Fig. 1E have longer delays after a 6 V shock than after a 20 V shock. Measurements were therefore made over a wide range of stimulating voltages in order to obtain a reliable minimum latency. Administration of sulfonamide increased synaptic delays in jaundiced rats further. Two-tailed t-tests, with correction for unequal variance, were used to determine the significance of the differences in synaptic delays among animal groups. The means of 4 groups of VCN neurons' minimum synaptic delays are compared in Table I. Mean minimal synaptic delays systematically increase with expected free bilirubin. Sulfa injections in the unjaundiced rats did not change minimal synaptic delays. The mean minimal latency in homozygotes was significantly higher than that of heterozygous controls. Sulfa injections in homozygotes increased the mean minimal latency further. The increase in latency in jaundiced Gunn rats is not likely to arise from a decreased conduction velocity. At about 10 m/s TM, it takes 0.02 ms for action potentials to be propagated from the stimulating electrodes to the terminals in the VCN (200 Hm). To account for a difference of 1.0 ms between normal and severely abnormal latencies, the conduction velocity would have to decrease from about 10 to 0.2 m/s. Such slow conduction is not known in myelinated fibers14; conduction would probably be blocked under such circumstances '3. Furthermore, anatomical studies give no indication of abnormalities in auditory nerve fibers that could account for such drastic reduction in the conduction velocity 1. More probably, the increase in latency arises from a slowing in the presynaptic events. The monosynaptic EPSPs are the result of the activation of kainate receptors 21, which are unlikely to be associated with a second-messenger system 8. If bilirubin were to interfere with postsynaptic receptors, rise times, not latencies, of EPSPs would be altered. It seems likely, therefore, that the lengthening of transmission from 0.7 to 2.0 ms in jaundiced rats results from changes in presynaptic events. In cells with EPSPs whose minimum latencies were abnormally long, all detected, converging EPSPs must have had to be delayed. Minimum latencies represent responses to shocks which are well above threshold and in most, if not all, cases
represent responses to several converging auditory nerve fibers 11. Bilirubin could interfere with the release of neurotransmitter by making complexes with phospholipids at the presynaptic terminals 3'2°. Bilirubin binds sphingomyelin and pure gangliosides with an affinity 5-25 times higher than other lipids 2°. These lipids are particularly abundant in the outer leaflet of the synaptosomal membrane. Furthermore, bilirubin binds synaptosomes from young animals more effectively than those from mature animals, especially at slightly acid pH 2°. The Gunn rats were chosen at ages between 2 and 3 weeks when the homozygotes O)') have the greatest bilirubin level of 12-16 mg/dl in serum 6. The latencies of synaptic responses to the auditory inputs in the murine VCN are longer and more variable before the age of 12 days 23. It is possible that elevated levels of bilirubin retard the neural development of some cells in homozygous Gunn rats, resulting in longer latencies than in heterozygous littermates of comparable ages. The present results are consistent with measurements of brainstem evoked responses to click stimuli in vivo. Shapiro and H e c o x 18'19 have shown that average brainstem responses from homozygous animals had increased wave I - I I intervals, reduced wave II and 1II amplitudes, and abnormal wave morphology in comparison with those in normal littermates. If wave I represents the invasion of the cochlear nuclei by activity in auditory nerve fibers and wave II represents activity in the cochlear nucleus, the lengthening of the interval between them in the jaundiced Gunn rat is what would be expected if synaptic delays are abnormally long. Furthermore, wave II is often split as if two populations of neurons respond at two different times, the latency of the response in one of the populations being normal and the other abnormally long. Also consistent with the present results is that in jaundiced Gunn rats intervals between waves II and III, I and II, and I and III increased two hours after sulfonamide injections 17. We thank Drs. Brugge, Shapiro, Odell and WhitIon for helpful suggestions and criticisms. The work was supported by N I H grants 17590 and 12732.
197 1 Brugge, J.F., Shapiro, S.M. and Smith, P.H., Conditions of the cochlear nuclei of the hyperbilirubinemic Gunn rat, Ass. Res. Otolaryngol. Abstr., (1987) 97-98. 2 Carbone, J.V. and Grodsky, G.M., Constitutional nonhemolytic hyperbilirubinemia in the rat: defect of bilirubin conjugation, Proc. Soc. Exp. Biol. Med., 94 (1957) 461-463. 3 Eriksen, E., Danielsen, H. and Brodersen, R., Bilirubinliposome interaction, J. Biol. Chem., 256 (1981) 42694274. 4 Gunn, C.K., Hereditary acholuric jaundice, J. Hered., 29 (1938) 137-139. 5 Gunn, C.K., Hereditary acholuric jaundice in the rat, Can. Med. Assoc. J., 50 (1944) 230-237. 6 Johnson, L., Sarmiento, F., Blanc, W.A. and Day, R., Kernicterus in rats with an inherited deficiency of glucuronyl transferase, Am. J. Dis. Child., 97 (1959) 591-608. 7 Lathe, G.H. and Walker, M., The synthesis of bilirubin glucuronide in animal and human liver, Biochem. J., 70 (1958) 705-712. 8 Mayer, M.L. and Westbrook, G.L., The physiology of excitatory amino acids in the vertebrate central nervous system, Prog. Neurobiol., 28 (1987) 197-276. 9 Odell, G.B., The dissociation of bilirubin from albumin and its clinical implications, J. Pediatr., 55 (1959) 268-279. 10 Oertel, D., Synaptic responses and electrical properties of cells in brain slices of the mouse anteroventral cochlear nucleus, J. Neurosci., 3 (1983) 2043-2053. 11 Oertel, D., Use of brain slices in the study of the auditory system: spatial and temporal summation of synaptic inputs in cells in the anteroventral cochlear nucleus of the mouse, J. Acoust. Soc. Am., 78 (1985) 328-333. 12 Oertel, D. and Wu, S.H., Morphology and physiology of cells in slice preparations of the dorsal cochlear nucleus of mice, J. Comp. Neurol., 283 (1989) 228-247.
13 Ramon, F., Joyner, R.W. and Moore, J.W., Propagation of action potentials in inhomogeneous axon regions, Fed. Proc., 34 (1975) 1357-1363. 14 Ritchie, J.M., On the relation between fibre diameter and conduction velocity in myelinated nerve fibers, Proc. R. Soc. Lond. B, 217 (1982) 29-35. 15 Rose, A.L. and Wisniewski, 'H., Acute bilirubin encephalopathy induced with sulfadimethoxine in Gunn rats, J. Neuropathol. Exp. Neurol., 38 (1979) 152-164. 16 Schutta, H.S. and Johnson, L., Clinical signs and morphologic abnormalities in Gunn rats treated with sulfadimethoxine, J. Pediatr., 75 (1969) 1070-1079. 17 Shapiro, S.M., Acute brainstem auditory evoked potential abnormalities in jaundiced Gunn rats given sulfonamide, Pediatr. Res., in press. 18 Shapiro, S.M. and Hecox, K.E., Brainstem auditory evoked potentials in jaundiced Gunn rats, Ann. Otol. RhinoL Laryngol., in press. 19 Shapiro, S.M. and Hecox, K.E., Development of brainstem auditory evoked potentials in heterozygous and homozygous jaundiced Gunn rats, Dev. Brain Res., 41 (1988) 147-157. 20 Vazquez, J., Garcia-Calvo, M., Valdivieso, F., Mayor, F. and Mayor, F. Jr., Interaction of bilirubin with the synaptosomal plasma membrane, J. Biol. Chem., 263 (1988) 1255-1265. 21 Wickesberg, R.E. and Oertel, D., Auditory nerve neurotransmitter acts on a kainate receptor, Brain Research, 486 (1989) 39-48. 22 Wu, S.H. and Oertel, D., Intracellular injection with horseradish peroxidase of physiologically characterized stellate and bushy cells in slices of mouse anteroventral cochlear nucleus, J. Neurosci., 4 (1984) 1577-1588. 23 Wu, S.H. and Oertel, D., Maturation of synapses and electrical properties, Hearing Res., 30 (1987) 99-110.