Both, the PDE2A inhibitor PF-999 [1] and the PDE9A inhibitor Bay 73-6691 [2] increased hippocampal LTP, but in contrast to PDE2A inhibition, PDE9A inhibition not only enhances early and late LTP, but even transforms early LTP into late LTP. Regarding effects on hippocampal PPF, only the PDE2A inhibitor but not the PDE9A inhibitor was able to modulate presynaptic function, indicating that PDE2A is localized at the presynaptic side whereas PDE9A might be located at the postsynaptic side.

Both inhibitors showed a dose-dependent increase of cGMP levels in mouse hippocampus after oral application, but exhibited no effect on cAMP levels. Memory performance could be improved by both inhibitors in the T-maze continuous alternation task using pharmacologically impaired mice or in the object location task using APP-transgenic Tg2576 mice.