The past, present, and future of phosphodiesterase-4 modulation for age-induced memory loss

The purpose of this chapter is to highlight the state of progress for phosphodiesterase-4 (PDE4) modulation as a potential therapeutic for psychiatric illness, and to draw attention to particular hurdles and obstacles that must be overcome in future studies to develop PDE4-mediated therapeutics. Pathological and non-pathological related memory loss will be the focus of the chapter; however, we will at times also touch upon other psychiatric illnesses like anxiety and depression. First, we will provide a brief background of PDE4, and the rationale for its extensive study in cognition. Second, we will explore fundamental differences in individual PDE4 subtypes, and then begin to address differences between pathological and non-pathological aging. Alterations of cAMP/PDE4 signaling that occur within normal vs. pathological aging, and the potential for PDE4 modulation to combat these alterations within each context will be described. Finally, we will finish the chapter with obstacles that have hindered the field, and future studies and alternative viewpoints that need to be addressed. Overall, we hope this chapter will demonstrate the incredible complexity of PDE4 signaling in the brain, and will be useful in forming a strategy to develop future PDE4-mediated therapeutics for psychiatric illnesses.