Differential changes in induced seizures after hippocampal treatment of rats with an antisense oligodeoxynucleotide to the GABA(A) receptor gamma2 subunit.

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain. Impairment of GABAergic neurotransmission may be involved in the pathogenesis of epileptic phenomena. We have previously characterized biochemical and histological changes following unilateral intrahippocampal infusion of a phosphorothioate antisense oligodeoxynucleotide to the GABA(A) receptor gamma2 subunit in rats in vivo. The aim of the present study was to investigate the behavioral changes of rats following unilateral hippocampal antisense 'knockdown' of the GABA(A) receptor gamma2 subunit. Antisense, but not mismatch control oligodeoxynucleotide treated rats had a significant weight loss (10%) during 6 d of treatment. Antisense treated rats exhibited no changes in spontaneous behavior, including anxiety-like behavior as measured in the social interaction test, compared to mismatch oligodeoxynucleotide treated rats. However, antisense treated rats developed pronounced changes in induced seizure activity. Seizures induced by subcutaneously injected pentylenetetrazol were markedly accentuated in antisense treated rats compared to treatment naive rats, whereas mismatch treated rats showed a lower seizure score than that of naive rats. Antisense treated rats had a significantly elevated threshold for seizures induced by electrical stimulation in the maximal electroshock seizure threshold test. The results suggest that intrahippocampal infusion of antisense oligodeoxynucleotide to the GABA(A) receptor gamma2 subunit leads to specific alterations in the sensitivity to induced seizures. The results are viewed as consequences of selective down-regulation of GABA(A) receptors and diminished inhibitory neurotransmission in the hippocampus.