Control of neuronal excitability by GSK-3beta: Epilepsy and beyond

Glycogen synthase kinase 3beta (GSK-3 beta) is an enzyme with a variety of cellular functions in addition to the regulation of glycogen metabolism. In the central nervous system, different intracellular signaling pathways converge on GSK-3 beta through a cascade of phosphorylation events that ultimately control a broad range of neuronal functions in the development and adulthood. In mice, genetically removing or increasing GSK-3 beta cause distinct functional and structural neuronal phenotypes and consequently affect cognition. Precise control of GSK-3 beta activity is important for such processes as neuronal migration, development of neuronal morphology, synaptic plasticity, excitability, and gene expression. Altered GSK-3 beta activity contributes to aberrant plasticity within neuronal circuits leading to neurological, psychiatric disorders, and neurodegenerative diseases. Therapeutically targeting GSK-3 beta can restore the aberrant plasticity of neuronal networks at least in animal models of these diseases. Although the complete repertoire of GSK-3 beta neuronal substrates has not been defined, emerging evidence shows that different ion channels and their accessory proteins controlling excitability, neurotransmitter release, and synaptic transmission are regulated by GSK-3 beta, thereby supporting mechanisms of synaptic plasticity in cognition. Dysregulation of ion channel function by defective GSK-3 beta activity sustains abnormal excitability in the development of epilepsy and other GSK-3 beta-linked human diseases.