A Role for Phosphodiesterase 11A (PDE11A) in the Formation of Social Memories and the Stabilization of Mood

Abstract

The most recently discovered 3′,5′-cyclic nucleotide phosphodiesterase family is the Phosphodiesterase 11 (PDE11) family, which is encoded by a single gene PDE11A. PDE11A is a dual-specific PDE, breaking down both cAMP and cGMP. There are four PDE11A splice variants (PDE11A1–4) with distinct tissue expression profiles and unique N-terminal regulatory regions, suggesting that each isoform could be individually targeted with a small molecule or biologic. PDE11A4 is the PDE11A isoform expressed in brain and is found in the hippocampal formation of humans and rodents. Studies in rodents show that PDE11A4 mRNA expression in brain is, in fact, restricted to the hippocampal formation (CA1, possibly CA2, subiculum, and the adjacently connected amygdalohippocampal area). Within the hippocampal formation of rodents, PDE11A4 protein is expressed in neurons but not astrocytes, with a distribution across nuclear, cytoplasmic, and membrane compartments. This subcellular localization of PDE11A4 is altered in response to social experience in mouse, and in vitro studies show the compartmentalization of PDE11A4 is controlled, at least in part, by homodimerization and N-terminal phosphorylation. PDE11A4 expression dramatically increases in the hippocampus with age in the rodent hippocampus, from early postnatal life to late aging, suggesting PDE11A4 function may evolve across the lifespan. Interestingly, PDE11A4 protein shows a 3–10-fold enrichment in the rodent ventral hippocampal formation (VHIPP; a.k.a. anterior in primates) versus dorsal hippocampal formation (DHIPP). Consistent with this enrichment in VHIPP, studies in knockout mice show that PDE11A regulates the formation of social memories and the stabilization of mood and is a critical mechanism by which social experience feeds back to modify the brain and subsequent social behaviors. PDE11A4 likely controls behavior by regulating hippocampal glutamatergic, oxytocin, and cytokine signaling, as well as protein translation. Given its unique tissue distribution and relatively selective effects on behavior, PDE11A may represent a novel therapeutic target for neuropsychiatric, neurodevelopmental, or age-related disorders. Therapeutically targeting PDE11A4 may be a way to selectively restore aberrant cyclic nucleotide signaling in the hippocampal formation while leaving the rest of the brain and periphery untouched, thus, relieving deficits while avoiding unwanted side effects.

Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer’s disease

“…PDE11A4 is the only PDE with restricted expression in hippocampal areas, which are affected in AD [27]. Both variants identi ed in this study affect PDE11A4 isoforms though a loss of function mechanism.…”

Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour

“…This suggests that if Tyr727Cys PDE11A is the causal variant at this locus then it is an activating mutation. PDE11A is expressed in the hippocampus and it has been suggested as a potential biological target for interventions in neuropsychiatric disorders 49 .…”

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…Hence, although PDE10A catalytic activity is not directly affected by this PTM, cyclic nucleotide levels should increase within this compartment due to the absence of PDE10. Preliminary evidence also suggests that PDE11A4 can similarly be shuttled between membrane and cytosolic compartments by virtue of phosphorylation of N-terminal serines, although this is likely by virtue of altering protein-protein interactions as opposed to a direct insertion into the membrane (275). PKA phosphorylation of PDE4D3 drives an association with the mAKAP signaling complex to evoke rapid signal termination in the muscle compartment (276), which may have therapeutic implications given that polymorphisms in the PDE4D3-mAKAP binding site lead to a higher susceptibility to cardiovascular disease (277).…”