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Volume 17, Number 3,
Issue of February 1, 1997
pp. 951-959
Copyright ©1997 Society for Neuroscience
Calpain Activation Contributes to Dendritic Remodeling after
Brief Excitotoxic Injury In Vitro
Received Aug. 16, 1996; revised Nov. 7, 1996; accepted Nov. 8, 1996.
Brian T. Faddis,
M. Josh Hasbani, and
Mark P. Goldberg
Departments of Neurology and Anatomy and Neurobiology, Center for
the Study of Nervous System Injury, Washington University School of
Medicine, St. Louis, Missouri 63110
The calcium-dependent protease calpain may contribute to neuronal
death in acute neurological insults and may be activated very early in
the neuronal injury cascade. We assessed the role of calpain in a model
of rapid, reversible dendritic injury in murine cortical cultures.
Brief sublethal NMDA exposure (10-30 µM for 10 min)
resulted in focal swellings, or varicosities, along the length of
neuronal dendrites as visualized with the lipophilic membrane tracer
DiI or with immunostaining using antibodies to the somatodendritic
protein MAP2. These varicosities appeared within minutes of NMDA
exposure and recovered spontaneously within 2 hr after NMDA removal.
Addition of the calpain inhibitors MDL28,170, calpain inhibitors I and
II, and leupeptin (all 1-100 µM) had little effect on
the development of NMDA-induced dendrite injury. However, the
resolution of varicosities was substantially delayed by addition of
calpain inhibitors after sublethal excitotoxic exposure. Using Western
blots and immunocytochemistry, we observed reactivity for a
calpain-specific spectrin proteolytic fragment during the period of
recovery from dendritic swelling, but not during its formation.
Spectrin breakdown product immunoreactivity could be blocked by the
calpain inhibitor MDL28,170 and appeared in neuronal cell
bodies and neurites in a time course that paralleled dendritic
recovery. These observations suggest that calcium-dependent proteolysis
contributes to recovery of dendritic structure after NMDA exposure.
Calpain activation is not necessarily detrimental and may play a role
in dendritic remodeling after neuronal injury.
Key words:
excitotoxicity;
calpain;
neuronal injury;
cell culture;
cytoskeleton;
glutamate;
spectrin
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