EXPERIMENTAL NEUROLOGY 106,41-51(1%@) Extracellular Potassium Activity and Axonal Conduction in Spinal Cord of the Myelin-Deficient Mutant Rat WISE YOUNG, JACK ROSENBLUTH, JOAN C. WOJAK, KAORU SAKATANI, AND HYOUN KIM Departments of Neurosurgery, Physiology &Biophysics and Rehabilitation Medicine, New York University School of Medicine, New York, New York We recorded somatosensory evoked potentials (SEPs), extracellular K+ ionic activity ([K+],), and K+ clearance rates in the spinal cords of 14 myelin-de- ficient mutant rats and 16 normal male littermates at 16-41 days after birth. Tested under pentobarbital an- esthesia (25 mg/kg ip) and hypothermic conditions (32- 34’C), myelin-deficient rats had longer cortical SEP la- tencies (67 + 20 ms) compared to those in normal sib- lings (48 + 15 ms; P < 0.05). Mean baseline [K+], levels were 2.6 + 0.5 mM in myelin-deficient rats and 2.6 + 0.8 n&in normal siblings. Clearance times of KC1 so- lutions injected into the spinal cord were biphasic and exponential. The mean initial and secondary exponen- tial half-times were 1.0 + 0.5 and 2.7 + 1.7 min for my- elin-deficient rats and 0.8 ? 0.4 and 3.6 + 3.2 min for normal siblings. Repetitive sciatic nerve stimulation (2-20 Hz, 2- to 6-s trains) produced l-3 mM transient [K+], rises in thoracic and lumbar cords of myelin-defi- cient rats. The [K+], rises were largest in the dorsal spi- nal cord at 200-500 pm depth. The normal siblings had smaller or no stimulus-induced [K+], rises. In myelin- deficient rats, injection of 1 mM 4-aminopyridine (4- AP) solution into the thoracic spinal cord completely suppressed the stimulus-induced [K+], and markedly in- creased spinal and cortical SEP amplitudes for several hours. In the normal siblings, the 4-AP injections tran- siently blocked spinal conduction for 20-30 min but thereafter enhanced cortical SEP amplitudes for 2-3 h. We conclude that sciatic nerve stimulation produces spinal cord [K+], rises in myelin-deficient rat larger than those in the normal siblings, that the [K+], tran- sients represent increased K+ release rather than im- paired K+ clearance, and that the K+ ions come from 4- AP blockable sources. o 1999 Academic PWS, I~C. INTRODUCTION Myelin is virtually absent in the central nervous sys- tem of the myelin-deficient mutant rat (4). Except for the myelin deficiency, the brains and spinal cords of these rats appear anatomically normal. Yet, the myelin- deficient rats manifest severe neurological abnormali- ties beginning in the second or third postnatal week. By the fourth week, they develop generalized tonic seizures culminating in death within a few days. It has been hy- pothesized previously (11, 12) that the neurological ab- normalities in these rats, particularly the seizures, are due to increased spontaneous activity in myelin-defi- cient central fiber tracts. Such activity may arise from ephaptic activation of quiescent axons, depolarization due to extracellular K+ accumulation, or both. In this study, we recorded somatosensory evoked po- tentials (SEPs) and spinal cord extracellular K+ ionic activity ( [Kfle) in myelin-deficient rats and normal lit- termates at 16-41 days after birth. We also measured extracellular K+ clearance rates and observed the effects of locally injected 4-aminopyridine (4-AP), a blocker of voltage-sensitive K+ channels, on [K3+18 and SEPs. The myelin-deficient rats had slower somatosensory conduc- tion, compared to their unaffected siblings. Spinal cord [K+], baselines and clearance rates did not differ be- tween the two groups. Sciatic nerve stimulation pro- duced l-3 mA4 rises of [K’le in thoracic and lumbar spi- nal cords of the myelin-deficient rats, compared to smaller or no rise in the unaffected littermates. Local injections of 1 mM 4-aminopyridine prevented the sti- mulus-induced [K+], rises and markedly enhanced SEP amplitudes in both groups. These results suggest that the myelin-deficient rats have greater activity-induced Kf release from 4-AP blockable K+ sources. METHODS Animal Preparation Male juvenile rats (16-41 days old) were selected from litters produced by heterozygous female Wistar rats bred with normal male Wistar rats. The disease is not mani- fest at birth, but mutant male offsprings develop a tremor at approximately 2 weeks and seizures at 3 weeks; they die by 4 to 5 weeks of age. The mutant rats and normal male littermates (“normal siblings”) were usually studied in pairs. The rats were anesthetized with 25 mg/kg of pento- barbital given intraperitoneally (supplemented with 10 41 0014-4686/89 $3.00 Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.