SGK1.1 activation causes early seizure termination via effects on M-current

Armas-Capote, N.; Maglio, L. E.; Perez-Atencio, L.; Martin-Batista, E.; Reboreda, A.; Barios, J. A.; Hernandez, G.; Alvarez de la Rosa, D.; Lamas, J. A.; Barril, L. C.; Giraldez, T.

doi:10.1101/520775

bioRxiv · 10.1101/520775

SGK1.1 activation causes early seizure termination via effects on M-current

Armas-Capote, N.·Maglio, L. E.·Perez-Atencio, L.·Martin-Batista, E.·Reboreda, A.·Barios, J. A.·Hernandez, G.·Alvarez de la Rosa, D.·Lamas, J. A.·Barril, L. C.·Giraldez, T.

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Abstract

Early termination of status epilepticus affords protection against brain damage and associated pathologies. Regulation of Kv7.2/7.3 potassium channels, underlying the neuronal M-current, is key for seizure control. This conductance is maintained during initiation of action potentials, affecting neuronal excitability and thus inhibiting epileptic discharges. The M-current is upregulated by the neuronal isoform of the serum and glucocorticoid-regulated kinase SGK1 (SGK1.1). We tested whether SGK1.1 is an anticonvulsant factor using the kainic acid (KA) model of acute seizures in a transgenic mouse model with expression of a constitutively active form of the kinase. Our results demonstrate that SGK1.1 confers robust protection against seizures associated to lower mortality levels, independently of sex or genetic background. SGK1.1-dependent protection results in reduced number, shorter duration, and early termination of EEG seizures. At the cellular level, it is associated to increased M-current amplitude mediated by Nedd4-2 phosphorylation, leading to decreased excitability of hippocampal CA1 neurons without alteration of basal synaptic transmission. Altogether, our results reveal that SGK1.1-mediated M-current upregulation in the hippocampus is a key component of seizure resistance in the KA epileptic paradigm, suggesting that regulation of this anticonvulsant pathway may improve adverse outcomes to status epilepticus, constituting a potential target for antiepileptic drugs.

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Armas-Capote, N., Maglio, L. E., Perez-Atencio, L., Martin-Batista, E., Reboreda, A., Barios, J. A., Hernandez, G., Alvarez de la Rosa, D., Lamas, J. A., Barril, L. C., Giraldez, T.. 2019-01-15. SGK1.1 activation causes early seizure termination via effects on M-current. https://doi.org/10.1101/520775

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