PT - JOURNAL ARTICLE AU - Tsao , Jack W. AU - George, Edwin B. AU - Griffin, John W. TI - Temperature Modulation Reveals Three Distinct Stages of Wallerian Degeneration AID - 10.1523/JNEUROSCI.19-12-04718.1999 DP - 1999 Jun 15 TA - The Journal of Neuroscience PG - 4718--4726 VI - 19 IP - 12 4099 - http://www.jneurosci.org/content/19/12/4718.short 4100 - http://www.jneurosci.org/content/19/12/4718.full SO - J. Neurosci.1999 Jun 15; 19 AB - 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°C. At 25°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°C the CAPs were minimal at 2 d. When the temperature of wild-type nerves was raised to 37°C after 24–72 hr at 25°C, degeneration occurred within the subsequent 24 hr. Wld nerves, too, were preserved longer at 25°C but, on return to 37°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 μm 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.