Alterations in neuronal gamma-aminobutyric acid(A) receptor responsiveness in genetic models of seizure susceptibility with different expression patterns.
The genetically epilepsy-prone rat (GEPR) is a unique animal model of seizure predisposition with substrains (i.e., GEPR-NE, GEPR-3, and GEPR-9) that exhibit different seizure patterns in response to the same stimulus. Among many deficits identified in these animals, reduced responses to GABA(A) receptor agonists have been described in several brain regions of the GEPR-9. However, few studies have quantitatively analyzed this difference in responsiveness or have examined and compared the responsiveness of GEPR-3 neurons with the other strains. Using intracellular recording, we determined and compared the responsiveness of Purkinje neurons from GEPR-3 animals with those of control (both Sprague-Dawley and GEPR-NE) and GEPR-9 rats at different developmental ages. In GEPR-9 animals, the EC(50) value for GABA and muscimol was shifted 3-fold to the right, with no reduction in maximum. In contrast, GEPR-3 animals showed a significant reduction in the maximum hyperpolarizing response to only GABA and muscimol with no change in the EC(50) values. Responsiveness to glutamate, aspartate, norepinephrine, and diazepam was unchanged in both strains, indicating that the change in responsiveness was highly selective for GABA(A) receptor agonists. Changes in responsiveness in animals <15 days of age suggests that deficits in GABAergic function exist before the development of seizure susceptibility. In addition, the data are the first to reveal that the GEPR-3 and GEPR-9 exhibit different changes in GABA(A) receptor function and may provide significant insight into the cellular mechanism underlying differences between these two strains.
Molnar
L R
LR
Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9223, USA.
Fleming
W W
WW
Taylor
D A
DA
D000367:Age Factors; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D009118:Muscimol / Q000494:pharmacology; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid