Src/CK2/PTEN-Mediated GluN2B and CREB Dephosphorylations Regulate the Responsiveness to AMPA Receptor Antagonists in Chronic Epilepsy Rats

Both α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) have been reported as targets for treatment of epilepsy. To investigate the roles and interactions of AMPAR and NMDAR in ictogenesis of epileptic hippocampus, we analyzed AMPAR antagonists (perampanel and GYKI 52466)-mediated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulation and glutamate ionotropic receptor NMDA type subunit 2B (GluN2B) tyrosine (Y) 1472 phosphorylation in epilepsy rats. Both perampanel and GYKI 52466 increased PTEN expression and its activity (reduced phosphorylation), concomitant with decreased activities (phosphorylations) of Src family-casein kinase 2 (CK2) signaling pathway. Compatible with these, they also restored the upregulated GluN2B Y1472 and Ca2+/cAMP response element-binding protein (CREB) serine (S) 133 phosphorylations and surface expression of glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) to basal level in the epileptic hippocampus. These effects of perampanel and GYKI 52466 are observed in responders (whose seizure activities are responsive to AMPAR antagonists), but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). Therefore, our findings suggest that Src/CK2/PTEN-mediated GluN2B Y1472 and CREB S133 regulations may be one of the responsible signaling pathways for the generation of refractory seizures in non-responders to AMPAR antagonists.

PTEN Is Required for The Anti-Epileptic Effects of AMPA Receptor Antagonists in Chronic Epileptic Rats

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is one of the ligand-gated ion channels for glutamate, which is an important player in the generation and spread of seizures. The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphorylation. Paradoxically, AMPAR expression and its phosphorylation level are decreased in the epileptic hippocampus. Therefore, the roles of AMPAR in seizure onset and neuronal hyperexcitability in ictogenesis remain to be elucidated. In the present study, we found that AMPAR antagonists (perampanel and GYKI 52466) decreased glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) surface expression in the epileptic rat hippocampus. They also upregulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and restored to basal levels the upregulated phosphoinositide 3-kinase (PI3K)/AKT1 phosphorylations. Dipotassium bisperoxovanadium(pic) dihydrate (BpV(pic), a PTEN inhibitor) co-treatment abolished the anti-epileptic effects of perampanel and GYKI 52466. Therefore, our findings suggest that PTEN may be required for the anti-epileptic effects of AMPAR antagonists.