Seizure-related regulation of GABAA receptors in spontaneously epileptic rats

• Seizure activity affects the plasma membrane expression and function of GABAARs.
• Seizure frequency might be associated with a reduction in the efficiency of inhibitory function.
• Increased levels of GABAAR at the plasma membrane might be a compensatory mechanism to maintain inhibitory function.

In this study, we analyzed the impact that spontaneous seizures might have on the plasma membrane expression, composition and function of GABAA receptors (GABAARs). For this, the tissue of chronically epileptic rats was collected within 3 h of seizure occurrence (≤ 3 h group) or at least 24 h after seizure occurrence (≥ 24 h group). A retrospective analysis of seizure frequency revealed that selecting animals on the bases of seizure proximity also grouped animals in terms of overall seizure burden with a higher seizure burden observed in the ≤ 3 h group. A biochemical analysis showed that although animals with more frequent/recent seizures (≤ 3 h group) had similar levels of GABAAR at the plasma membrane they showed deficits in inhibitory neurotransmission. By contrast, the tissue obtained from animals experiencing infrequent seizures (≥ 24 h group) had increased plasma membrane levels of GABAAR and showed no deficit in inhibitory function. Together, our findings offer an initial insight into the molecular changes that might help to explain how alterations in GABAAR function can be associated with differential seizure burden. Our findings also suggest that increased plasma membrane levels of GABAAR might act as a compensatory mechanism to more effectively maintain inhibitory function, repress hyperexcitability and reduce seizure burden. This study is an initial step towards a fuller characterization of the molecular events that trigger alterations in GABAergic neurotransmission during chronic epilepsy.