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

Brain. 2022 Jul 29;145(7):2332-2346. doi: 10.1093/brain/awac037.


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.

Keywords: AMPK; GABA; epilepsy; metabolism; thalamocortical.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

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


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