Abstract: The second messengers 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) modulate molecular pathways that are involved in a large variety of cellular processes. In the brain, these processes include neurogenesis, neuronal differentiation, activation and function of microglia, and synaptic plasticity, finally resulting in memory formation. All this implies that the homeostasis of these two molecules must be tightly regulated both at their synthesis—that is catalyzed by adenylate/ guanylate cyclase—and at their degradation by phosphodiesterases (PDE). The PDE family is composed of 11 subfamilies of proteins that are all expressed in the brain at different levels (Delhaye et al., 2021).