Vol. 295, Issue 3, 1258-1266, December 2000

Alterations in Neuronal -Aminobutyric Acid_A Receptor Responsiveness in Genetic Models of Seizure Susceptibility with Different Expression Patterns¹

Lance R. Molnar², William W. Fleming and David A. Taylor

Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, West Virginia

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 EC₅₀ 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 EC₅₀ 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.