Systemic injection of
kainic acid (KA) does not cause neuronal pathology in limbic structures in rat brain prior to postnatal day (PND) 21. The present study tested if the development of the pathogenic response is associated with the maturation of a link between seizure activity and
polyamine metabolism. Pathology was assessed with histological techniques and with the binding of [3H]Ro5-4864, a
ligand for the peripheral type
benzodiazepine binding sites (PTBBS), a marker of glial cell proliferation. In agreement with previous results, peripherally administered
kainate at doses sufficient to induce intense behavioral
seizures produced a loss of Nissl staining in hippocampus after PND 21 but not at earlier ages. The pattern of neuronal damage observed after PND 21 resembled that found in adult animals: extensive losses of Nissl staining in area CA3 of hippocampus and in piriform cortex, more modest effects in CA1 and sparing of the granule cells of the dentate gyrus. Similarly, no increase in [3H]Ro5-4864 binding as a result of KA administration was observed in hippocampus and piriform cortex until PND 21.
Ornithine decarboxylase (ODC) activity and
putrescine levels were high in the neonatal brain and decreased to reach adult values by PND 21. KA-induced seizure activity did not significantly alter both variables until PND 21. After PND 21, ODC activity and
putrescine levels markedly increased 16 h after KA-induced seizure activity in hippocampus and piriform cortex. The magnitude of the effects increased between PND 21 and PND 30, at which point the changes in both parameters were comparable to those found in adults.
Polyamines stimulate the activity of the
calcium-dependent
proteases calpain in brain fractions and may increase
calpain-mediated proteolysis in situ. In accord with this,
kainate-induced breakdown of
spectrin, a preferred substrate of
calpain, measured 16 h after KA injection followed a developmental curve parallel to that for
kainate-induced increases in
putrescine levels. These results indicate that the onset of vulnerability to seizure activity triggered by
kainic acid is correlated with the development of an ODC/
polyamine response to the
seizures and further support a critical role for the ODC/
polyamine pathway in neuronal pathology following a variety of insults.