title: Seizure-related regulation of GABAA receptors in spontaneously epileptic rats.
abstract: 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 3h of seizure occurrence (≤3h group) or at least 24h after seizure occurrence (≥24h 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 ≤3h group. A biochemical analysis showed that although animals with more frequent/recent seizures (≤3h 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 (≥24h 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.
authors.affiliation: Department of Pediatrics, Division of Neurology, University of Colorado School of Medicine, Aurora, CO, 80045 USA; Translational Epilepsy Research Program, University of Colorado Aurora CO 80045, USA. Electronic address: marco.gonzalez@ucdenver.edu.
authors.forename: Marco I
authors.initials: MI
authors.lastname: González
authors.affiliation: Department of Pediatrics, Division of Neurology, University of Colorado School of Medicine, Aurora, CO, 80045 USA; Translational Epilepsy Research Program, University of Colorado Aurora CO 80045, USA.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Grabenstatter
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Translational Epilepsy Research Program, University of Colorado Aurora CO 80045, USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Cea-Del Rio
authors.affiliation: Department of Pediatrics, Division of Neurology, University of Colorado School of Medicine, Aurora, CO, 80045 USA; Translational Epilepsy Research Program, University of Colorado Aurora CO 80045, USA.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Cruz Del Angel
authors.affiliation: Department of Pediatrics, Division of Neurology, University of Colorado School of Medicine, Aurora, CO, 80045 USA; Translational Epilepsy Research Program, University of Colorado Aurora CO 80045, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Carlsen
authors.affiliation: Department of Pediatrics, Division of Neurology, University of Colorado School of Medicine, Aurora, CO, 80045 USA.
authors.forename: Rick P
authors.initials: RP
authors.lastname: Laoprasert
authors.affiliation: Department of Pediatrics, Division of Neurology, University of Colorado School of Medicine, Aurora, CO, 80045 USA; Translational Epilepsy Research Program, University of Colorado Aurora CO 80045, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: White
authors.affiliation: Department of Pediatrics, Division of Neurology, University of Colorado School of Medicine, Aurora, CO, 80045 USA; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Translational Epilepsy Research Program, University of Colorado Aurora CO 80045, USA.
authors.forename: Molly M
authors.initials: MM
authors.lastname: Huntsman
authors.affiliation: Department of Pediatrics, Division of Neurology, University of Colorado School of Medicine, Aurora, CO, 80045 USA; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Translational Epilepsy Research Program, University of Colorado Aurora CO 80045, USA; Children's Hospital Colorado, Aurora, CO 80045, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Brooks-Kayal
mesh_terms: D000818:Animals; D019921:Biotinylation; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000633:toxicity; D009474:Neurons / Q000187:drug effects; D010862:Pilocarpine / Q000633:toxicity; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D007555:Isoxazoles; D018721:Muscarinic Agonists; D011810:Quinoxalines; D011963:Receptors, GABA-A; D010862:Pilocarpine; C056723:FG 9041; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine; C015542:gaboxadol
keywords: Epilepsy; Epileptogenesis; GABA(A)R regulation; Spontaneous seizures