GSK3? inhibition promotes synaptogenesis in Drosophila and mammalian neurons.

ABSTRACT: The PI3K-dependent activation of AKT results in the inhibition of GSK3? 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? and, consequently, pharmacological strategies based on GSK3? 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? in synaptogenesis. In flies, the genetic inhibition of the shaggy-encoded GSK3? 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? 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?, a feature that must be considered in the context of human adult neurogenesis and pharmacological treatments for Alzheimer's disease based on GSK3? antagonists.

SUBMITTER: Cuesto G 

PROVIDER: S-EPMC4357437 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature