Mice deficient in phosphodiesterase-4A display anxiogenic-like behavior

Psychopharmacology (Berl). 2014 Aug;231(15):2941-54. doi: 10.1007/s00213-014-3480-y. Epub 2014 Feb 22.


Rationale: Phosphodiesterases (PDEs) are a super family of enzymes responsible for the halting of intracellular cyclic nucleotide signaling and may represent novel therapeutic targets for treatment of cognitive disorders. PDE4 is of considerable interest to cognitive research because it is highly expressed in the brain, particularly in the cognition-related brain regions. Recently, the functional role of PDE4B and PDE4D, two of the four PDE4 subtypes (PDE4A, B, C, and D), in behavior has begun to be identified; however, the role of PDE4A in the regulation of behavior is still unknown.

Objectives: The purpose of this study was to characterize the functional role of PDE4A in behavior.

Methods: The role of PDE4A in behavior was evaluated through a battery of behavioral tests using PDE4A knockout (KO) mice; urine corticosterone levels were also measured.

Results: PDE4A KO mice exhibited improved memory in the step-through-passive-avoidance test. They also displayed anxiogenic-like behavior in elevated-plus maze, holeboard, light-dark transition, and novelty suppressed feeding tests. Consistent with the anxiety profile, PDE4A KO mice had elevated corticosterone levels compared with wild-type controls post-stress. Interestingly, PDE4A KO mice displayed no change in object recognition, Morris water maze, forced swim, tail suspension, and duration of anesthesia induced by co-administration of xylazine and ketamine (suggesting that PDE4A KO may not be emetic).

Conclusions: These results suggest that PDE4A may be important in the regulation of emotional memory and anxiety-like behavior, but not emesis. PDE4A could possibly represent a novel therapeutic target in the future for anxiety or disorders affecting memory.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / physiopathology*
  • Behavior, Animal / physiology*
  • Corticosterone / urine
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / deficiency*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / physiology*
  • Depression / physiopathology
  • Emotions / physiology
  • Hippocampus / physiopathology
  • Male
  • Memory / physiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / physiology
  • Neuropsychological Tests
  • Protein Isoforms
  • Spatial Memory / physiology


  • Protein Isoforms
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Pde4a protein, mouse
  • Corticosterone