AMPK-mediated potentiation of GABAergic signalling drives hypoglycaemia-provoked spike-wave seizures.
Brain
; 145(7): 2332-2346, 2022 07 29.
Article
em En
| MEDLINE
| ID: mdl-35134125
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Epilepsia Tipo Ausência
/
Hipoglicemia
Idioma:
En
Revista:
Brain
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos