Reduced GABAB receptor subunit expression and paired-pulse depression in a genetic model of absence seizures.
Neocortical networks play a major role in the genesis of generalized spike-and-wave (SW) discharges associated with absence seizures in humans and in animal models, including genetically predisposed WAG/Rij rats. Here, we tested the hypothesis that alterations in GABA(B) receptors contribute to neocortical hyperexcitability in these animals. By using Real-Time PCR we found that mRNA levels for most GABA(B(1)) subunits are diminished in epileptic WAG/Rij neocortex as compared with age-matched non-epileptic controls (NEC), whereas GABA(B(2)) mRNA is unchanged. Next, we investigated the cellular distribution of GABA(B(1)) and GABA(B(2)) subunits by confocal microscopy and discovered that GABA(B(1)) subunits fail to localize in the distal dendrites of WAG/Rij neocortical pyramidal cells. Intracellular recordings from neocortical cells in an in vitro slice preparation demonstrated reduced paired-pulse depression of pharmacologically isolated excitatory and inhibitory responses in epileptic WAG/Rij rats as compared with NECs; moreover, paired-pulse depression in NEC slices was diminished by a GABA(B) receptor antagonist to a greater extent than in WAG/Rij rats further suggesting GABA(B) receptor dysfunction. In conclusion, our data identify changes in GABA(B) receptor subunit expression and distribution along with decreased paired-pulse depression in epileptic WAG/Rij rat neocortex. We propose that these alterations may contribute to neocortical hyperexcitability and thus to SW generation in absence epilepsy.
Merlo
D
D
Istituto Superiore di Sanità, Dipartimento di Biologia Cellulare e Neuroscienze, 00161 Rome, Italy.
Mollinari
C
C
Inaba
Y
Y
Cardinale
A
A
Rinaldi
A M
AM
D'Antuono
M
M
D'Arcangelo
G
G
Tancredi
V
V
Ragsdale
D
D
Avoli
M
M
D000818:Animals; D004195:Disease Models, Animal; D004594:Electrophysiology; D004832:Epilepsy, Absence / Q000503:physiopathology*; D019579:Neocortex / Q000166:cytology / Q000502:physiology*; D009433:Neural Inhibition / Q000502:physiology; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D018080:Receptors, GABA-B / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; D018080:Receptors, GABA-B