The promise of cyclic AMP modulation to restore cognitive function in neurodevelopmental disorders.

Cyclic AMP (cAMP) is a key regulator of synaptic function and is dysregulated in both neurodevelopmental (NDD) and neurodegenerative disorders. Due to the ease of diffusion and promiscuity of downstream effectors, cAMP signaling is restricted within spatiotemporal domains to localize activation. Among the best-studied mechanisms is the feedback inhibition of cAMP-dependent protein kinase (PKA) activity by phosphodiesterases 4 (PDE4s) at synapses controlling neuronal plasticity, which is largely regulated by PDE4D. In fact, genetic variants in genes for multiple PKA subunits and PDE4D lead to NDDs. Here, we discuss the rationale for choosing PDE4D as a candidate for the design of selective allosteric inhibitors and the recent advances in clinical trials. These new compounds improve cognitive function in preclinical animal models due to improved selectivity and more physiological inhibition of the active enzyme. We also discuss opportunities for better understanding of PDE4D function in general, and for the development of next-generation inhibitors.