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

Abstract

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.

• Authors: Kathryn A Salvati, Matthew L Ritger, Pasha A Davoudian, Finnegan O'Dell, Daniel R Wyskiel, George M P R Souza, Adam C Lu, Edward Perez-Reyes, Joshua C Drake, Zhen Yan, Mark P Beenhakker
• Journal: Brain : a journal of neurology (Brain) Vol. 145 Issue 7 Pg. 2332-2346 (07 29 2022) ISSN: 1460-2156 [Electronic] England
• PMID: 35134125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.

Chemical References

• Receptors, GABA-B
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Epilepsy, Absence (metabolism)
• Humans
• Hypoglycemia (chemically induced, metabolism)
• Receptors, GABA-B (metabolism)
• Seizures
• Thalamus