AMPK-mediated potentiation of GABAergic signalling drives hypoglycaemia-provoked spike-wave seizures.

Autor:	Salvati KA; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.; Epilepsy Research Laboratory and Weil Institute for Neurosciences, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA., Ritger ML; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Davoudian PA; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.; MD-PhD Program, Yale University School of Medicine, New Haven, CT 06520, USA., O'Dell F; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Wyskiel DR; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Souza GMPR; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Lu AC; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Perez-Reyes E; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Drake JC; Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.; The Robert M. Berne Center for Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Yan Z; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.; The Robert M. Berne Center for Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.; Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Beenhakker MP; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2022 Jul 29; Vol. 145 (7), pp. 2332-2346.
DOI:	10.1093/brain/awac037
Abstrakt:	Metabolism regulates neuronal activity and modulates the occurrence of epileptic seizures. Here, using two rodent models of absence epilepsy, we show that hypoglycaemia increases the occurrence of spike-wave seizures. We then show that selectively disrupting glycolysis in the thalamus, a structure implicated in absence epilepsy, is sufficient to increase spike-wave seizures. We propose that activation of thalamic AMP-activated protein kinase, a sensor of cellular energetic stress and potentiator of metabotropic GABAB-receptor function, is a significant driver of hypoglycaemia-induced spike-wave seizures. We show that AMP-activated protein kinase augments postsynaptic GABAB-receptor-mediated currents in thalamocortical neurons and strengthens epileptiform network activity evoked in thalamic brain slices. Selective thalamic AMP-activated protein kinase activation also increases spike-wave seizures. Finally, systemic administration of metformin, an AMP-activated protein kinase agonist and common diabetes treatment, profoundly increased spike-wave seizures. These results advance the decades-old observation that glucose metabolism regulates thalamocortical circuit excitability by demonstrating that AMP-activated protein kinase and GABAB-receptor cooperativity is sufficient to provoke spike-wave seizures. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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