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 neurotransmission has been implicated in the development of epileptic seizures. To determine whether seizures affect GABA(A)-receptor gene transcription in vivo, a transgenic mouse line carrying a lacZ-fusion gene driven by GABA(A)-receptor delta-subunit promoter and upstream sequences was subjected to pentylenetetrazol (PTZ)-induced seizures. After injection of a single convulsive dose of PTZ, the activity of the delta-subunit promoter, as monitored by beta-galactosidase immunohistochemistry, was increased selectively in neurons of layers II-IV of neocortex. In contrast, mice kindled by repeated administration of initially subconvulsive doses of PTZ did not show a change in transgene expression, even shortly after the last PTZ-induced seizure. These results show that transient changes in transcription of the GABA(A)-receptor delta-subunit gene occur after acute seizures, but not after kindling. The limited responsiveness of the GABA(A)-receptor delta-subunit promoter after repeated stimulation may reflect an inappropriate adaptation of cellular responses to recurrent excitation, thereby contributing to the development of seizure disorders.
Penschuck
S
S
Institute of Pharmacology, ETH and University of Zurich, Switzerland.
Lüscher
B
B
Fritschy
J M
JM
Crestani
F
F
D000818:Animals; D001921:Brain / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007696:Kindling, Neurologic; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D010433:Pentylenetetrazole; D011401:Promoter Regions, Genetic; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D001616:beta-Galactosidase / Q000096:biosynthesis
D011963:Receptors, GABA-A; D011993:Recombinant Fusion Proteins; D001616:beta-Galactosidase; D010433:Pentylenetetrazole