Alterations in neuronal gamma-aminobutyric acid(A) receptor responsivenessin genetic models of seizure susceptibility with different expression patterns

The genetically epilepsy-prone rat (GEPR) is a unique animal model of seizu re 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) rec eptor agonists have been described in several brain regions of the GEPR-9. However, few studies have quantitatively analyzed this difference in respon siveness or have examined and compared the responsiveness of GEPR-3 neurons with the other strains. Using intracellular recording, we determined and c ompared the responsiveness of Purkinje neurons from GEPR-3 animals with tho se of control (both Sprague-Dawley and GEPRNE) and GEPR-9 rats at different developmental ages. In GEPR-9 animals, the EC50 value for GABA and muscimo l was shifted 3-fold to the right, with no reduction in maximum. In contras t, GEPR-3 animals showed a significant reduction in the maximum hyperpolari zing response to only GABA and muscimol with no change in the EC50 values. Responsiveness to glutamate, aspartate, norepinephrine, and diazepam was un changed in both strains, indicating that the change in responsiveness was h ighly 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 ar e 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 c ellular mechanism underlying differences between these two strains.