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

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dc.contributor.authorSalvati, Kathryn A.en
dc.contributor.authorRitger, Matthew L.en
dc.contributor.authorDavoudian, Pasha A.en
dc.contributor.authorO'Dell, Finneganen
dc.contributor.authorWyskiel, Daniel R.en
dc.contributor.authorSouza, George M. P. R.en
dc.contributor.authorLu, Adam C.en
dc.contributor.authorPerez-Reyes, Edwarden
dc.contributor.authorDrake, Joshua C.en
dc.contributor.authorYan, Zhenen
dc.contributor.authorBeenhakker, Mark P.en
dc.date.accessioned2022-10-24T13:32:20Zen
dc.date.available2022-10-24T13:32:20Zen
dc.date.issued2022-07-29en
dc.description.abstractMetabolism 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.en
dc.description.notesThis study was funded by intramural support from the NIH funding agencies NINDS (R01 NS099586), NIAMS (R01 AR050429), NIDDK (K99/R00-AG057825), NIGMS (T32G007055) and the American Heart Association (#19POST34430205).en
dc.description.sponsorshipNIH funding agency NINDS [R01 NS099586]; NIH funding agency NIAMS [R01 AR050429]; NIH funding agency NIDDK [K99/R00-AG057825]; NIH funding agency NIGMS [T32G007055]; American Heart Association [19POST34430205]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1093/brain/awac037en
dc.identifier.eissn1460-2156en
dc.identifier.issn0006-8950en
dc.identifier.issue7en
dc.identifier.pmid35134125en
dc.identifier.urihttp://hdl.handle.net/10919/112263en
dc.identifier.volume145en
dc.language.isoenen
dc.publisherOxford University Pressen
dc.rightsCreative Commons Attribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectepilepsyen
dc.subjectmetabolismen
dc.subjectAMPKen
dc.subjectGABAen
dc.subjectthalamocorticalen
dc.titleAMPK-mediated potentiation of GABAergic signalling drives hypoglycaemia-provoked spike-wave seizuresen
dc.title.serialBrainen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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