Phosphodiesterase‐1b deletion confers depression‐like behavioral resistance separate from stress‐related effects in mice

• Published in: Genes, brain and behavior brain and behavior, 2017-11, Vol.16 (8), p.756-767
• Main Authors: Hufgard, J. R., Williams, M. T., Vorhees, C. V.
• Format: Article
• Language: English
• Subjects: Animals; Antidepressants; Brain - metabolism; Brain - physiology; Ca2+/calmodulin-dependent phosphodiesterase; Critical period; Cyclic Nucleotide Phosphodiesterases, Type 1 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 1 - metabolism; Dentate gyrus; Depression - genetics; Depression - physiopathology; Dexamethasone; Drug development; Female; forced swim test; Genotype & phenotype; Hedonic response; Learned helplessness; Locomotor activity; Male; Mental depression; Mice; Mice, Inbred C57BL; Neostriatum; Phenotype; Phosphodiesterase; phosphodiesterase‐1b; Rodents; Stress, Psychological - genetics; Stress, Psychological - physiopathology; striatum; Substantia nigra; Sucrose; tail suspension test; Tamoxifen
• ISSN: 1601-1848; 1601-183X
• DOI: 10.1111/gbb.12391

Phosphodiesterase‐1b (Pde1b) is highly expressed in striatum, dentate gyrus, CA3 and substantia nigra. In a new Floxed Pde1b × CreCMV global knockout (KO) mouse model, we show an immobility‐resistance phenotype that recapitulates that found in constitutive Pde1b KO mice. We use this new mouse model to show that the resistance to acute stress‐induced depression‐like phenotype is not the product of changes in locomotor activity or reactivity to other stressors (learned helplessness, novelty suppressed feeding or dexamethasone suppression), and is not associated with anhedonia using the sucrose preference test. Using tamoxifen inducible Cre, we show that the immobility‐resistant phenotype depends on the age of induction. The effect is present when Pde1b is Reduced from conception, P0 or P32, but not if reduced as adults (P60). We also mapped regional brain expression of PDE1B protein and of the Cre driver. These data add to the suggestion that PDE1B may be a target for drug development with therapeutic potential in depression alone or in combination with existing antidepressants. We created a new Floxed phosphodiesterase‐1b (Pde1b) × CreCMV global knockout (KO) mouse model and we show it to be immobility resistant in forced swim and tail suspension tests. We use this new mouse to show that the phenotype is not stress‐related using tests of learned helplessness, novelty suppressed feeding or dexamethasone suppression. Neither the former tests nor anhedonic using the sucrose preference test showed differences. Using tamoxifen inducible Cre, we show that the immobility‐resistant phenotype depends on age. The effect is present when Pde1b is deleted from conception, P0 or P32, but not if deleted in adults (P60). We mapped brain expression of PDE1B protein and Cre driver. The data suggest that PDE1B may be a target for drug development with potential antidepressant effects.