GSK3[beta] Inhibition Promotes Synaptogenesis in Drosophila and Mammalian Neurons

The PI3K-dependent activation of AKT results in the inhibition of GSK3[beta] in most signaling pathways. These kinases regulate multiple neuronal processes including the control of synapse number as shown for Drosophila and rodents. Alzheimer disease's patients exhibit high levels of circulating GSK3[beta] and, consequently, pharmacological strategies based on GSK3[beta] antagonists have been designed. The approach, however, has yielded inconclusive results so far. Here, we carried out a comparative study in Drosophila and rats addressing the role of GSK3[beta] in synaptogenesis. In flies, the genetic inhibition of the shaggy-encoded GSK3[beta] increases the number of synapses, while its upregulation leads to synapse loss. Likewise, in three weeks cultured rat hippocampal neurons, the pharmacological inhibition of GSK3[beta] increases synapse density and Synapsin expression. However, experiments on younger cultures (12 days) yielded an opposite effect, a reduction of synapse density. This unexpected finding seems to unveil an age- and dosage-dependent differential response of mammalian neurons to the stimulation/inhibition of GSK3[beta], a feature that must be considered in the context of human adult neurogenesis and pharmacological treatments for Alzheimer's disease based on GSK3[beta] antagonists.