Unraveling the Effects of GSK-3ß Isoform Modulation against Limbic Seizures and in the 6 Hz Electrical Kindling Model for Epileptogenesis.

ABSTRACT

Two closely related glycogen synthase kinase-3 (GSK-3) isoforms have been identified in mammals GSK-3α and GSK-3ß. GSK-3ß is the most prominent in the central nervous system and was previously shown to control neuronal excitability. We previously demonstrated that indirubin and its structural analogue and the nonselective GSK-3 inhibitor BIO-acetoxime exerted anticonvulsant effects in acute seizure models in zebrafish, mice, and rats. We here examined for the first time the anticonvulsant effect of TCS2002, a specific and potent inhibitor of GSK-3ß, in two models for limbic seizures the pilocarpine rat model for focal seizures and the acute 6 Hz corneal mouse model for refractory seizures. Next, we additionally used the 6 Hz kindling model to establish differences in seizure susceptibility and seizure progression in mice that either overexpress human GSK-3ß (GSK-3ß OE) or lack GSK-3ß (GSK-3ß-/-) in neurons. We demonstrate that TCS2002 exerts anticonvulsant actions against pilocarpine- and 6 Hz-evoked seizures. Compared to wild-type littermates, GSK-3ß OE mice are less susceptible to seizures but are more rapidly kindled. Interestingly, compared to GSK-3ß+/+ mice, neuronal GSK-3ß-/- mice show increased susceptibility to 6 Hz-induced seizures. These contrasting observations suggest compensatory neurodevelopmental mechanisms that alter seizure susceptibility in GSK-3ß OE and GSK-3ß-/- mice. Although the pronounced anticonvulsant effects of selective and acute GSK-3ß inhibition in the 6 Hz model identify GSK-3ß as a potential drug target for pharmacoresistant seizures, our data on the sustained disruption of GSK-3ß activity in the transgenic mice suggest a role for GSK-3 in kindling and warrants further research into the long-term effects of selective pharmacological GSK-3ß inhibition.