ACTIVATION OF THE GABA(A)-RECEPTOR DELTA-SUBUNIT GENE PROMOTER FOLLOWING PENTYLENETETRAZOLE-INDUCED SEIZURES IN TRANSGENIC MICE

An impairment of GABA(A)-receptor-mediated inhibitory neurotransmissio n has been implicated in the development of epileptic seizures. To det ermine whether seizures affect GABA(A)-receptor gene transcription in vivo, a transgenic mouse line carrying a lacZ-fusion gene driven by GA BA(A)-receptor delta-subunit promoter and upstream sequences was subje cted to pentylenetetrazol (PTZ)-induced seizures. After injection of a single convulsive dose of PTZ, the activity of the delta-subunit prom oter, as monitored by beta-galactosidase immunohistochemistry, was inc reased selectively in neurons of layers II-IV of neocortex. In contras t, mice kindled by repeated administration of initially subconvulsive doses of PTZ did not show a change in transgene expression, even short ly after the last PTZ-induced seizure. These results show that transie nt changes in transcription of the GABA(A)-receptor delta-subunit gene occur after acute seizures, but not after kindling. The limited respo nsiveness of the GABA(A)-receptor delta-subunit promoter after repeate d stimulation may reflect an inappropriate adaptation of cellular resp onses to recurrent excitation, thereby contributing to the development of seizure disorders. (C) 1997 Elsevier Science B.V.