Inhibition of acetylcholinesterase and phosphodiesterase-9A has differential effects on hippocampal early and late LTP

Donepezil is the current standard symptomatic treatment of mild-to-moderate Alzheimer's disease (AD) patients. It aims to compensate for the deficit in cholinergic neurotransmission by blocking acetylcholinesterase (AChE) and thus increases the concentration of extracellular acetylcholine. However, experience from clinical practice demonstrated that AChE inhibitors only have moderate treatment effects. As a potential new approach for memory enhancement, inhibition of specific phosphodiesterases (PDEs) has gained attention. Among those are PDE9A inhibitors which increase the levels of the second messenger cyclic guanosine monophosphate (cGMP) intracellularly. In order to gain more insight into the potential impact of extracellularly acting AChEs and intracellularly acting PDE9A inhibitors on synaptic plasticity, we analyzed the effects of the AChE inhibitor donepezil and the PDE9A inhibitor BAY 73-6691 on long-term potentiation (LTP) in rat hippocampal slices, a widely accepted cellular experimental model of memory formation. Generally, LTP can be differentiated into an early and a late form, being protein-synthesis independent and protein-synthesis dependent, respectively. Donepezil was found to increase early LTP, but did not affect late LTP. In contrast, BAY 73-6691 demonstrated enhancing effects on both early and late LTP and even transformed early into late LTP. Furthermore, it was shown that this transformation into late LTP was dependent on the NO-cGMP-PKG pathway. In conclusion, this study demonstrates that BAY 73-6691 exhibits a stronger effect in enhancing and prolonging LTP than donepezil suggesting that PDE9 inhibition might be more efficacious in enhancing learning and memory. ► Experience with AChE inhibitors raised questions regarding efficacy in AD patients. ► PDE inhibitors might represent alternative approaches to treat cognitive dysfunction. ► Testing AChE inhibitor donepezil and PDE9A inhibitor BAY 73-6691 on LTP. ► Inhibition of PDE9A is more efficient in enhancing LTP than inhibition of AChE. ► PDE9A inhibition might be an attractive approach to treat cognitive dysfunction.