PT  - JOURNAL ARTICLE
AU  - Natalia Armas-Capote
AU  - Laura E. Maglio
AU  - Leonel Pérez-Atencio
AU  - Elva Martin-Batista
AU  - Antonio Reboreda
AU  - Juan A. Barios
AU  - Guadalberto Hernandez
AU  - Diego Alvarez de la Rosa
AU  - José Antonio Lamas
AU  - Luis C. Barrio
AU  - Teresa Giraldez
TI  - SGK1.1 activation causes early seizure termination via effects on M-current
AID  - 10.1101/520775
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 520775
4099  - http://biorxiv.org/content/early/2019/02/08/520775.short
4100  - http://biorxiv.org/content/early/2019/02/08/520775.full
AB  - 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 could act as 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.