Although there is evidence that astrocytes support neuronal function, the contribution of astrocytes to seizure onset and termination is not known. To determine whether there are changes in seizure susceptibility or neuronal damage when the ability of astrocytes to generate
ATP is reduced, 0.5 nmol of
fluorocitrate (FC) was injected into the right ventricle. Injection of FC alone did not produce electrographic or behavioral
seizures and did not stress or injure neurons or astrocytes, as measured with
silver stain and immunohistochemistry for HSP32 or HSP72. However, in animals pretreated with FC, administration of
kainic acid, at a dose that does not initiate
seizures in control animals (7 mg/kg), caused wet dog shakes and neuronal damage in the hilus. Wet dog shakes did not cause any neuronal damage in control animals. If the dose of FC was increased to 0.75 nmol, then subsequent administration of the same dose of
kainic acid (7 mg/kg) caused stage 3-5
seizures. Injection of FC also reduced the dose of
pilocarpine needed to produce
seizures. Given simultaneously with FC,
isocitrate, which bypasses the biochemical inhibition of
aconitase, blocked the effects of FC in both
kainic acid and
pilocarpine treated animals. The data demonstrate that inhibition of
aconitase in astrocytes lowers the doses of both
kainic acid and
pilocarpine that will cause behavioral
seizures and may increase neuronal vulnerability to
seizures.