PMID:25764078

Citation	Cuesto, G, Jordán-Álvarez, S, Enriquez-Barreto, L, Ferrús, A, Morales, M and Acebes, Á (2015) GSK3β inhibition promotes synaptogenesis in Drosophila and mammalian neurons. PLoS ONE 10:e0118475
Abstract	The PI3K-dependent activation of AKT results in the inhibition of GSK3β 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 GSK3β and, consequently, pharmacological strategies based on GSK3β 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 GSK3β in synaptogenesis. In flies, the genetic inhibition of the shaggy-encoded GSK3β increases the number of synapses, while its upregulation leads to synapse loss. Likewise, in three weeks cultured rat hippocampal neurons, the pharmacological inhibition of GSK3β 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 GSK3β, a feature that must be considered in the context of human adult neurogenesis and pharmacological treatments for Alzheimer's disease based on GSK3β antagonists.
Links	PubMed PMC4357437 Online version:10.1371/journal.pone.0118475
Keywords	Animals; Cells, Cultured; Drosophila Proteins/metabolism; Drosophila melanogaster/enzymology; Glycogen Synthase Kinase 3/metabolism; Hippocampus/cytology; Hippocampus/enzymology; Humans; Neurons/enzymology; Neurons/physiology; Rats; Signal Transduction; Synapses/enzymology; Synapses/physiology; Synapsins/metabolism; Up-Regulation
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:GSK3B		GO:0045886: negative regulation of synaptic growth at neuromuscular junction	ECO:0000315:		P		The nature of regulation is age dependent. In figure 6B,C Inhibition of GSK3 by AR and SB resulted in an increase in synapse density for older cultures (21 DIV). Younger Cultures had an inverse response.	complete CACAO 11247
RAT:GSK3B		GO:0045887: positive regulation of synaptic growth at neuromuscular junction	ECO:0000315:		P		The nature of regulation is age dependent. In figure 6D, Inhibition of GSK3 by AR and SB resulted in an decrease in synapse density for younger cultures (12 DIV).	complete CACAO 11248
DROME:SGG		GO:0045886: negative regulation of synaptic growth at neuromuscular junction	ECO:0000316:	UniProtKB:P91634	P		Figure 3 shows negative regulation of synapses in the larval Drosophila Neuromuscular junction regardless of the presence of upstream regulator PI3k. This is noted as a study of NMJ in the beginning of the discussion.	complete CACAO 11246

References

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