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

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 GABA(B)-receptor function, is a significant driver of hypoglycaemia-induced spike-wave seizures. We show that AMP-activated protein kinase augments postsynaptic GABA(B)-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 GABA(B)-receptor cooperativity is sufficient to provoke spike-wave seizures. Hypoglycaemia is an established trigger for absence seizures. Salvati et al. investigate the mechanism underlying this link, and show that activation of thalamic AMPK-a cellular sensor of intracellular ATP-promotes spike-wave activity in a rat model of absence epilepsy by potentiating GABA-B receptor signalling.

Automated summary

Metabolism plays a role in regulating neuronal activity and epileptic seizures. This study demonstrates that hypoglycemia increases the occurrence of spike-wave seizures in rodent models of absence epilepsy. The disruption of glycolysis in the thalamus, a structure associated with absence epilepsy, is shown to increase spike-wave seizures. The activation of thalamic AMP-activated protein kinase (AMPK) and the potentiation of GABA(B)-receptor signaling are identified as significant factors driving hypoglycemia-induced spike-wave seizures. The study also finds that the administration of metformin, an AMPK agonist, significantly increases spike-wave seizures.