Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition

Cognitive dysfunction is a core feature of dementia and a prominent feature inpsychiatric disease. As non-redundant regulators of intracellular cAMP gradients,phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant tolearning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is animportant phosphodiesterase in the hippocampal formation, is a major Disrupted inSchizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatricillness. To define the effects of specific inhibition of the PDE4B subtype, wegenerated mice with a catalytic domain mutant form of PDE4B (Y358C) that hasdecreased ability to hydrolyze cAMP. Structural modeling predictions of decreasedfunction and impaired binding with DISC1 were confirmed in cell assays. Phenotypiccharacterization of the PDE4B^Y358C mice revealed facilitatedphosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 andβ-Arrestin in hippocampus and amygdala. In behavioral assays,PDE4B^Y358C mice displayed decreased anxiety and increased exploration,as well as cognitive enhancement across several tests of learning and memory,consistent with synaptic changes including enhanced long-term potentiation andimpaired depotentiation ex vivo. PDE4B^Y358C mice alsodemonstrated enhanced neurogenesis. Contextual fear memory, though intact at24 h, was decreased at 7 days in PDE4B^Y358C mice, an effectreplicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMPsignaling by PDE4B in a very late phase of consolidation. No effect of thePDE4B^Y358C mutation was observed in the prepulse inhibition and forcedswim tests. Our data establish specific inhibition of PDE4B as a promisingtherapeutic approach for disorders of cognition and anxiety, and a putative targetfor pathological fear memory.