Systemic injection of
kainic acid (KA) in adult rat elicits a pattern of neuronal pathology which exhibits several features of human
temporal lobe epilepsy. KA-induced seizure activity is accompanied by the activation of the
calcium-dependent
protease calpain in limbic structures. In the present study, we evaluated the spatio-temporal activation of
calpain after the onset of seizure activity by immunohistochemistry using an antibody for the
spectrin breakdown product (
sbdp) generated by
calpain-mediated
spectrin proteolysis. In addition, we compared the changes in
sbdp immunoreactivity with those in immunoreactivity to subunits of the Glu/
AMPA receptors (GluR1 and GluR2/3). One hour after seizure onset,
sbdp accumulation was observed in selected interneurons in stratum oriens and in the hilus of the dentate gyrus. By 4 h,
sbdp immunoreactivity was prominent in dendritic fields of the hippocampus as well as in neurons in thalamus and piriform cortex. By 8 h,
sbdp immunoreactivity had disappeared from interneurons but was localized in pyramidal cell bodies in hippocampus. Intense labeling of cell bodies and dendritic fields persisted until 5 days following KA treatment. Changes in GluR subunit immunoreactivity were mirror images of those seen for
sbdp. In general, increased
sbdp immunoreactivity in dendritic fields was associated with decreased GluR1 immunoreactivity. However, increased
sbdp immunoreactivity in neuronal perikarya was also associated with increased GluR immunoreactivity. These results indicate that
calpain activation following seizure onset exhibits a specific spatio-temporal pattern, with activation in restricted interneurons preceding widespread activation in pyramidal neurons.
Calpain activation also precedes neuronal pathology and could thus represent an initial trigger for neuronal pathology. Finally, the results suggest that
calpain activation produces rapid alterations in GluR subunit properties which could be involved in the hyperexcitability observed following seizure activity.