Testing the disinhibition hypothesis of epileptogenesis in vivo and duringspontaneous seizures

The "disinhibition" hypothesis contends that (1) seizures begin when granul e cells in the dentate gyrus of the dorsal hippocampus are disinhibited and (2) disinhibition occurs because GABAergic interneurons are excessively in hibited by other GABAergic interneurons. We tested the disinhibition hypoth esis using the experimental model that inspired it-naturally epileptic Mong olian gerbils. To determine whether there is an excess of GABAergic interne urons in the dentate gyrus of epileptic gerbils, as had been reported previ ously, GABA immunocytochemistry, in situ hybridization of GAD67 mRNA, and t he optical fractionator method were used. There were no significant differe nces in the numbers of GABAergic interneurons. To determine whether granule cells in epileptic gerbils were disinhibited during the interictal period, IPSPs were recorded in vivo with hippocampal circuits intact in urethane-a nesthetized gerbils. The reversal potentials and conductances of IPSPs in g ranule cells in epileptic versus control gerbils were similar. To determine whether the level of inhibitory control in the dentate gyrus transiently d ecreases before seizure onset, field potential responses to paired-pulse pe rforant path stimulation were obtained from the dorsal hippocampus while ep ileptic gerbils experienced spontaneous seizures. Evidence of reduced inhib ition was found after, but not before, seizure onset, indicating that seizu res are not triggered by disinhibition in this region. However, seizure-ind uced depression of inhibition may amplify and promote the spread of seizure activity to other brain regions. These findings do not support the disinhi bition hypothesis and suggest that in this model of epilepsy seizures initi ate by another mechanism or at a different site.