Traumatic axonal injury results in biphasic calpain activation and retrograde transport impairment in mice.
Traumatic axonal injury (TAI) is one of the most important pathologies associated with closed head injury, and contributes to ensuing morbidity. The authors evaluated the potential role of calpains in TAI using a new model of optic nerve stretch injury in mice. Male C57BL/6 mice were anesthetized, surgically prepared, and subjected to a 2.0-mm optic nerve stretch injury (n = 34) or sham injury (n = 18). At various intervals up to 2 weeks after injury, optic nerves were examined for neurofilament proteins and calpain-mediated spectrin breakdown products using immunohistochemistry. In addition, fluorescent tracer was injected into the superior colliculi of mice 1 day before they were killed, to investigate the integrity of retrograde axonal transport to the retina. Optic nerve stretch injury resulted in persistent disruption of retrograde axonal transport by day 1, progressive accumulation and dephosphorylation of neurofilament protein in swollen and disconnected axons, and subsequent loss of neurofilament protein in degenerating axons at day 14. Calpains were transiently activated in intact axons in the first minutes to hours after stretch injury. A second stage of calpain-mediated proteolysis was observed at 4 days in axonal swellings, bulbs, and fragments. These data suggest that early calpain activation may contribute to progressive intraaxonal structural damage, whereas delayed calpain activation may be associated with axonal degeneration.
Saatman
Kathryn E
KE
Department of Neurosurgery, University of Pennsylvania, Philadelphia 19104, USA. saatman@mail.med.upenn.edu
Abai
Babak
B
Grosvenor
Ashley
A
Vorwerk
Christian K
CK
Smith
Douglas H
DH
Meaney
David F
DF
D000818:Animals; D001369:Axons / Q000378:metabolism; D001693:Biological Transport, Active; D002154:Calpain / Q000378:metabolism*; D020833:Diffuse Axonal Injury / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010447:Peptide Hydrolases / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism; D013049:Spectrin / Q000378:metabolism
D013049:Spectrin; D010447:Peptide Hydrolases; D002154:Calpain