Testing the disinhibition hypothesis of epileptogenesis in vivo and during spontaneous seizures.
The "disinhibition" hypothesis contends that (1) seizures begin when granule cells in the dentate gyrus of the dorsal hippocampus are disinhibited and (2) disinhibition occurs because GABAergic interneurons are excessively inhibited by other GABAergic interneurons. We tested the disinhibition hypothesis using the experimental model that inspired it-naturally epileptic Mongolian gerbils. To determine whether there is an excess of GABAergic interneurons in the dentate gyrus of epileptic gerbils, as had been reported previously, GABA immunocytochemistry, in situ hybridization of GAD67 mRNA, and the optical fractionator method were used. There were no significant differences 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-anesthetized gerbils. The reversal potentials and conductances of IPSPs in granule cells in epileptic versus control gerbils were similar. To determine whether the level of inhibitory control in the dentate gyrus transiently decreases before seizure onset, field potential responses to paired-pulse perforant path stimulation were obtained from the dorsal hippocampus while epileptic gerbils experienced spontaneous seizures. Evidence of reduced inhibition was found after, but not before, seizure onset, indicating that seizures are not triggered by disinhibition in this region. However, seizure-induced depression of inhibition may amplify and promote the spread of seizure activity to other brain regions. These findings do not support the disinhibition hypothesis and suggest that in this model of epilepsy seizures initiate by another mechanism or at a different site.
Departments of Comparative Medicine and Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305-5410, USA. psb@stanford.edu
P S
PS
Buckmaster
A L
AL
Jongen-Rêlo
S B
SB
Davari
E H
EH
Wong
D000818:Animals; D002452:Cell Count; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000209:etiology / Q000503:physiopathology*; D005849:Gerbillinae; D007395:Interneurons / Q000378:metabolism* / Q000473:pathology; D009433:Neural Inhibition / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D005680:gamma-Aminobutyric Acid