GABAA receptor antisense epilepsy: histological changes following infusion of antisense oligodeoxynucleotide to GABAA receptor gamma 2 subunit into rat hippocampus.

A deficiency of neuronal inhibition mediated by gamma-aminobutyric acid (GABA) via the GABAA receptor complex has been hypothesised to be a central factor in epileptogenesis. Intrahippocampal infusion of antisense oligodeoxynucleotide (ODN) to the GABAA receptor gamma 2 subunit in rats leads to electrographic limbic status epilepticus. In this model, epileptic phenomena are accompanied by loss of hippocampal neurones. The purpose of the present study was to investigate the time-course of morphological changes following hippocampal antisense 'knockdown' of the GABAA receptor gamma 2 subunit. gamma 2 subunit antisense ODN was infused continuously into the right hippocampus for periods between 1 and 5 days. After about 4 days of infusion, pronounced neurodegenerative changes were consistently observed within the ipsilateral hippocampus. In general, marked loss of CA3 pyramidal cells was found. The notion that the histological changes induced by the antisense ODN were specific to the applied ODN sequence was supported by the finding that a mismatch control ODN did not induce neurodegenerative changes, except for a small lesion in the immediate vicinity of the infusion site. Extensive ipsilateral hippocampal infiltration with monocytes and macrophages was a feature of antisense ODN infusion, but was considerably less pronounced after the infusion of control ODN. Immunocytochemistry using an antibody labeling glial fibrillary acidic protein (GFAP), revealed marked astroglial hypertrophy/proliferation after 4 days of antisense treatment, i.e., coincident with the development of neurodegeneration, in the ipsilateral hippocampus. At this time GFAP-immunoreactivity was also evident in the contralateral hippocampus, indicating contralateral spread of seizure activity.