Apr 4, 2020

Reduced neurosteroid potentiation of GABAA receptors in epilepsy and depolarized hippocampal neurons

Annals of Clinical and Translational Neurology
Suchitra JoshiLaura A Jansen

Abstract

Neurosteroids regulate neuronal excitability by potentiating γ-aminobutyric acid type-A receptors (GABARs). In animal models of temporal lobe epilepsy, the neurosteroid sensitivity of GABARs is diminished and GABAR subunit composition is altered. We tested whether similar changes occur in patients with epilepsy and if depolarization-induced increases in neuronal activity can replicate this effect. We determined GABAR α4 subunit expression in cortical tissue resected from pediatric epilepsy patients. Modulation of human GABARs by allopregnanolone and Ro15-4513 was measured in Xenopus oocytes using whole-cell patch clamp. To extend the findings obtained using tissue from epilepsy patients, we evaluated GABAR expression and modulation by allopregnanolone and Ro15-4513 in cultured rat hippocampal neurons exposed to high extracellular potassium (HK) to increase neuronal activity. Expression of α4 subunits was increased in pediatric cortical epilepsy specimens encompassing multiple pathologies. The potentiation of GABA-evoked currents by the neurosteroid allopregnanolone was decreased in Xenopus oocytes expressing GABARs isolated from epilepsy patients. Furthermore, receptors isolated from epilepsy but not control tissue were sensiti...Continue Reading

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Mentioned in this Paper

Sepranolone
Gamma-Aminobutyric Acid
Neurosteroids
Postsynaptic Current
Anticonvulsants
Epilepsy
Surface
Hippocampus (Brain)
Seizures
Evaluation

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