Altered expression of GABA(A) and GABA(B) receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus.
Epilepsy may result from altered transmission of the principal inhibitory transmitter GABA in the brain. Using in situ hybridization in two animal models of epileptogenesis, we investigated changes in the expression of nine major GABA(A) receptor subunits (alpha1, alpha2, alpha4, alpha5, beta1-beta3, gamma2 and delta) and of the GABA(B) receptor species GABA(B)R1a, GABA(B)R1b and GABA(B)R2 in 1) hippocampal kindling and 2) epilepsy following electrically-induced status epilepticus (SE). Hippocampal kindling triggers a decrease in seizure threshold without producing spontaneous seizures and hippocampal damage, whereas the SE model is characterized by spontaneous seizures and hippocampal damage. Changes in the expression of GABA(A) and GABA(B) receptor mRNAs were observed in both models, and compared with those seen in other models and in human temporal lobe epilepsy. The most prominent changes were a relatively fast (24 h after kindling and electrically-induced SE) and lasting (7 and 30 days after termination of kindling and SE, respectively) reduction of GABA(A) receptor subunit delta mRNA levels (by 43-78%) in dentate granule cells, accompanied by increases in mRNA levels of all three beta-subunits (by 8-79%) and subunit gamma2 (by 11-43%). Levels of the minor subunit alpha4 were increased by up to 60% in dentate granule cells in both animal models, whereas those of subunit alpha5 were decreased 24 h and 30 days after SE, but not after kindling. In cornu ammonis 3 pyramidal cells, downregulation of subunits alpha2, alpha4, alpha5, and beta1-3 was observed in the ventral hippocampus and of alpha2, alpha5, beta3 and gamma2 in its dorsal extension 24 h after SE. Similar but less pronounced changes were seen in sector cornu ammonis 1. Persistent decreases in subunit alpha2, alpha4 and beta2 transcript levels were presumably related to SE-induced cell loss. GABA(B) receptor expression was characterized by increases in GABA(B)R2 mRNA levels at all intervals after kindling and SE. The observed changes suggest substantial and cell specific rearrangement of GABA receptors. Lasting downregulation of subunits delta and alpha5 in granule cells and transient decreases in subunit alpha2 and beta1-3 mRNA levels in cornu ammonis 3 pyramidal cells are suggestive of impaired GABA(A) receptor-mediated inhibition. Persistent upregulation of subunits beta1-3 and gamma2 of the GABA(A) receptor and of GABA(B)R2 mRNA in granule cells, however, may result in activation of compensatory anticonvulsant mechanisms.
Nishimura
T
T
Department of Pharmacology, Innsbruck Medical University, Peter-Mayr-Str. 1a, 6020 Innsbruck, Austria.
Schwarzer
C
C
Gasser
E
E
Kato
N
N
Vezzani
A
A
Sperk
G
G
D000818:Animals; D001483:Base Sequence; D015342:DNA Probes; D004597:Electroshock; D006624:Hippocampus / Q000503:physiopathology*; D017403:In Situ Hybridization; D007696:Kindling, Neurologic / Q000473:pathology / Q000502:physiology*; D008969:Molecular Sequence Data; D021122:Protein Subunits / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics*; D018080:Receptors, GABA-B / Q000235:genetics*; D012640:Seizures / Q000145:classification / Q000503:physiopathology; D013226:Status Epilepticus / Q000209:etiology / Q000235:genetics*
D015342:DNA Probes; D021122:Protein Subunits; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B