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Browsing by Author "Salvati, Kathryn A."

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    AMPK-mediated potentiation of GABAergic signalling drives hypoglycaemia-provoked spike-wave seizures
    Salvati, Kathryn A.; Ritger, Matthew L.; Davoudian, Pasha A.; O'Dell, Finnegan; Wyskiel, Daniel R.; Souza, George M. P. R.; Lu, Adam C.; Perez-Reyes, Edward; Drake, Joshua C.; Yan, Zhen; Beenhakker, Mark P. (Oxford University Press, 2022-07-29)
    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.