The Phosphodiesterase 9 Inhibitor PF-04449613 Promotes Dendritic Spine Formation and Performance Improvement after Motor Learning.

The cyclic nucleotide cGMP is an intracellular second messenger with important roles in neuronal functions and animals' behaviors. The phosphodiesterases (PDEs) are a family of enzymes that hydrolyze the second messengers cGMP and cAMP. Inhibition of phosphodiesterase 9 (PDE9), a main isoform of PDEs hydrolyzing cGMP, has been shown to improve learning and memory as well as cognitive function in rodents. However, the role of PDE9 in regulating neuronal structure and function in vivo remains unclear. Here we used in vivo two-photon microscopy to investigate the effect of a selective PDE9 inhibitor PF-04449613 on the activity and plasticity of dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex. We found that administration of PF-04449613 increased calcium activity of dendrites and dendritic spines of layer V pyramidal neurons in mice under resting and running conditions. Chronic treatment of PF-04449613 over weeks increased dendritic spine formation and elimination under basal conditions. Furthermore, PF-04449613 treatment over 1-7 days increased the formation and survival of new spines as well as performance improvement after rotarod motor training. Taken together, our studies suggest that elevating the level of cGMP with the PDE9 inhibitor PF-04449613 increases synaptic calcium activity and learning-dependent synaptic plasticity, thereby contributing to performance improvement after learning.