Inhibition of PDE5 induces rapid non-genomic increase in hippocampal dendritic spines via specific kinases

Cyclic guanosine monophosphate (cGMP) is a typical neuromodulator that is used in neuronal synapses. Inhibitor of phosphodiesterase 5 (PDE5) could regulates signaling pathways by elevating cGMP levels. In the current study, we found that the treatments with tadalafil, a PDE5 inhibitor, for 2 h rapidly and non-genomically increased the total density of dendritic spines, using confocal imaging of Lucifer Yellow-injected hippocampal CA1 pyramidal neurons. Since inhibition of PDE5 elevates cGMP levels at synapses, we analyzed downstream nongenomic signaling. We analyzed the involvement of kinase signaling, because rapid postsynaptic modulation often involves kinase networks as observed from many investigations of synaptic functions. Upon co-treatments of PKG inhibitor (KT5823) with tadalafil, the spine increase was considerably blocked. In addition, co-treatments of GSK-3 inhibitor (I8) also blocked the spine increase induced by tadalafil. However, inhibitors of other representative synaptic kinases, including LIMK, Erk/MAPK, PKA, PKC and PI3K, did not suppress the tadalafil-induced spine increases. PDE5 inhibitors have attracted attention on their recovery effects from pathological damages, including memory improvement from cognitive impairment by Stroke, Amyloid beta accumulation and tau phosphorylation. The current finding of tadalafil function about rapid modulation of neural plasticity may add new elemental steps of anti-aging capacity against cognitive decline.