Temperature modulation reveals three distinct stages of Wallerian degeneration.
After peripheral nerve transection, axons distal to the cut site rapidly degenerate, a process termed Wallerian degeneration. In wild-type mice the compound action potential (CAP) disappears by 3 d. Previous studies have demonstrated that cold temperatures and lower extracellular calcium ion (Ca2+) concentrations can slow the rate of Wallerian degeneration. We have incubated isolated sciatic nerve segments from wild-type and C57BL/Wld mice (which carry a gene slowing Wallerian degeneration) in vitro at 25 and 37 degrees C. At 25 degrees C we found that the degeneration rate of wild-type axons was slowed dramatically, with the CAP preserved up to 7 d post-transection. In contrast, at 37 degrees C the CAPs were minimal at 2 d. When the temperature of wild-type nerves was raised to 37 degrees C after 24-72 hr at 25 degrees C, degeneration occurred within the subsequent 24 hr. Wld nerves, too, were preserved longer at 25 degrees C but, on return to 37 degrees C, degenerated promptly. Cooling the nerve within 12 hr after axotomy enhanced axonal preservation. Neither wild-type nor Wld nerves showed different degeneration rates when they were incubated with 250 microM or 5 or 10 mM extracellular Ca2+ for 1-2 d, suggesting that an abrupt increase in intracellular Ca2+ occurs at the time of axonal destruction. Wallerian degeneration, thus, appears to progress through three distinct stages. Initiation occurs at the time of injury with subsequent temperature-dependent and -independent phases. Nerves appear to remain intact and are able to exclude Ca2+ from entering until an as yet unknown process finally increases axolemmal permeability.
Tsao
J W
JW
Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland 21287, USA.
George
E B
EB
Griffin
J W
JW
D000818:Animals; D001369:Axons / Q000378:metabolism*; D019771:Axotomy; D001831:Body Temperature / Q000502:physiology*; D002118:Calcium / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D012584:Sciatic Nerve / Q000166:cytology / Q000503:physiopathology* / Q000601:surgery; D013997:Time Factors; D014855:Wallerian Degeneration / Q000503:physiopathology*
D002118:Calcium