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

Author:

Salvati Kathryn A12,Ritger Matthew L1,Davoudian Pasha A13ORCID,O’Dell Finnegan1,Wyskiel Daniel R1,Souza George M P R1,Lu Adam C1,Perez-Reyes Edward1,Drake Joshua C45,Yan Zhen1567,Beenhakker Mark P1ORCID

Affiliation:

1. Department of Pharmacology, University of Virginia School of Medicine , Charlottesville, VA 22908 , USA

2. Epilepsy Research Laboratory and Weil Institute for Neurosciences, Department of Neurological Surgery, University of California , San Francisco, San Francisco, CA 94143 , USA

3. MD-PhD Program, Yale University School of Medicine , New Haven, CT 06520 , USA

4. Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University , Blacksburg, VA 24061 , USA

5. The Robert M. Berne Center for Cardiovascular Research Center, University of Virginia School of Medicine , Charlottesville, VA 22908 , USA

6. Department of Medicine, University of Virginia School of Medicine , Charlottesville, VA , USA

7. Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine , Charlottesville, VA 22908 , USA

Abstract

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.

Funder

NIH

NINDS

NIAMS

NIDDK

NIGMS

American Heart Association

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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