Differential GABAA subunit expression following status epilepticus in seizure-prone and seizure-resistant rats: A putative mechanism for refractory drug response

Abstract

Purpose: Two rat strains were selectively bred to be prone (Fast) or resistant (Slow) to amygdala kindling. The first objective of this experiment was to determine whether that selection was specific to kindling or was sensitive more broadly to another seizure induction agent, kainic acid (KA). Second, we investigated whether these strains exhibit distinct molecular responses to KA with respect to GABAA receptor subunit expression. Methods: Development of status epilepticus (SE) was profiled in Fast and Slow rats injected with 20 mg/kg KA (i.p.). Two hours post-SE onset, rats received a sedative dose of sodium pentobarbital. Behavioral profiles included latency to SE, number of wet dog shakes (WDS), and number and duration of stage 3-5 generalized seizures. Rats were killed 24 h post-SE, and α1 and α4 mRNA levels were compared in the hippocampus and amygdala using QPCR. Results: Slow rats exhibited a much greater latency to SE onset (p < 0.01) and many more WDS (p < 0.01) than Fast rats. During SE, Fast rats spent more time in and exhibited more repeated bouts of generalized stage 3-5 seizures (p < 0.01) than Slow rats. Constitutive levels of α1 and α4 were not different between the strains in either structure and equivalent reductions in α4 were evident 24 h post-SE. However, while Fast rats showed KA-induced reductions in α1 in both structures, Slow rats showed significant elevations. Conclusions: Genetic selection for temporal lobe excitability, manifested as differential amygdala kindling rates, is paralleled by vulnerability to KA-induced SE. Further, these strains exhibited at least one opposing molecular response to SE, namely α1 expression. This finding may offer a putative mechanism through which seemingly similar epilepsies can be intractable in some patients but treatable in others. © International League Against Epilepsy.