GABA(A) receptor antisense epilepsy: Histological changes following infusion of antisense oligodeoxynucleotide to GABA(A) receptor gamma 2 subunit into rat hippocampus

A deficiency of neuronal inhibition mediated by gamma -aminobutyric acid (G ABA) via the GABAA receptor complex has been hypothesised to be a central f actor in epileptogenesis. Intrahippocampal infusion of antisense oligodeoxy nucleotide (ODN) to the GABAA receptor ya subunit in rats leads to electrog raphic limbic status epilepticus. In this model, epileptic phenomena are ac companied by loss of hippocampal neurones. The purpose of the present study was to investigate the time-course of morphological changes following hipp ocampal antisense 'knockdown' of the GABA(A) receptor gamma2 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, pronounc ed neurodegenerative changes were consistently observed within the ipsilate ral hippocampus. In general, marked loss of CA3 pyramidal cells was found T he notion that the histological changes induced by the antisense ODN were s pecific to the applied ODN sequence was supported by the finding that a mis match control ODN did not induce neurodegenerative changes, except for a sm all lesion in the immediate vicinity of the infusion site. Extensive ipsila teral 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 gli al fibrillary acidic protein (GFAP) revealed marked astroglial hypertrophy/ proliferation after 4 days of antisense treatment, i.e., coincident with th e development of neurodegeneration, in the ipsilateral hippocampus. At this time GFAP-immunoreactivity was also evident in the contralateral hippocamp us, indicating contralateral spread of seizure activity.