Neuronal apoptosis and reversible motor deficit in dominant-negative GSK-3 conditional transgenic mice

Increased glycogen synthase kinase-3 (GSK-3) activity is believed to contribute to the etiology of chronic disorders like Alzheimer's disease and diabetes, thus supporting therapeutic potential of GSK-3 inhibitors. However, sustained GSK-3 inhibition might induce tumorigenesis through beta-catenin-APC dysregulation. Besides, sustained in vivo inhibition by genetic means (constitutive knockout mice) revealed unexpected embryonic lethality due to massive hepatocyte apoptosis. Here, we have generated transgenic mice with conditional (tetracycline system) expression of dominant-negative-GSK-3 as an alternative genetic approach to predict the outcome of chronic GSK-3 inhibition, either per se, or in combination with mouse models of disease. By choosing a postnatal neuron-specific promoter, here we specifically address the neurological consequences. Tet/ DN-GSK-3 mice showed increased neuronal apoptosis and impaired motor coordination. Interestingly, DN-GSK-3 expression shut-down restored normal GSK-3 activity and re-established normal incidence of apoptosis and motor coordination. These results reveal the importance of intact GSK-3 activity for adult neuron viability and physiology and warn of potential neurological toxicity of GSK-3 pharmacological inhibition beyond physiological levels. Interestingly, the reversibility data also suggest that unwanted side effects are likely to revert if excessive GSK-3 inhibition is halted.