PMID:17700644

Citation	Zhang, HT, Huang, Y, Masood, A, Stolinski, LR, Li, Y, Zhang, L, Dlaboga, D, Jin, SL, Conti, M and O'Donnell, JM (2008) Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacology 33:1611-23
Abstract	Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression- and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4B-/-). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4B-/- mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4B-/- mice. Compared to PDE4B+/+ littermates, PDE4B-/- mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light-dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4B-/- mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4B-/- mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4B-/- mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior.
Links	PubMed PMC2728355 Online version:10.1038/sj.npp.1301537
Keywords	Analysis of Variance; Animals; Anxiety/blood; Anxiety/genetics; Anxiety/pathology; Anxiety/physiopathology; Avoidance Learning; Behavior, Animal; Brain/pathology; Brain/physiopathology; Bromodeoxyuridine/metabolism; Cell Proliferation; Corticosterone/blood; Cyclic Nucleotide Phosphodiesterases, Type 4/deficiency; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation/physiology; Hindlimb Suspension; Male; Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Phenotype; Reaction Time
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:Q3TTI9	Contributes to	GO:0004115: 3',5'-cyclic-AMP phosphodiesterase activity	ECO:0000112:		F		Figure 2 PDE4B−/− mice displayed decreases in PDE4B expression and PDE4 activity and an increase in neurogenesis. (a) Mice deficient in PDE4B (−/−) displayed a decrease in the expression of PDE4B1/3, but did not show any changes in that of PDE4A (A5) and PDE4D (D3) in cerebral cortices, relative to PDE4B wild-type (+ / +) controls. PDE4B heterozygous (+/ −) mice displayed intermediate expression in PDE4B1/3 relative to PDE4B + / + and PDE4B −/− mice. The tissues were homogenized and immunoprecipitated as described in the Methods section. The proteins of PDE4B1/3, PDE4A5, and PDE4D3 were detected by western blot analysis. Molecular weights of the PDE4 variants are shown in parentheses (Dlaboga et al, 2006). (b and c) PDE4B−/− mice displayed decreased PDE4 activity, but no change in non-PDE4 activity in both the cerebral cortex (b) and the amygdala (c). In contrast, these mice exhibited decreases in total PDE activity in the amygdala and a tendency toward decreased total PDE activity in the cerebral cortex. PDE4 activity was obtained by subtracting non-PDE4 (ie rolipram-sensitive PDE) activity from total PDE activity. (d and e) Representative photomicrographs of the hippocampal dentate gyrus from PDE4B+ / + (d) and PDE4B−/− (e) immunofluorescent staining for BrdU-positive cells (arrowhead), which were predominantly localized in the subgranular zone (SGZ) and within the granule cell layer (GCL). (f–h) Representative photomicrographs of cells double immunostaining (h; yellow) for Tuj1 (f; green) and BrdU (g; red) in the GCL of the dentate gyrus of the hippocampus from PDE4B−/− mice. (i) Quantification of BrdU and Tuj1 double-positive cells. PDE4B−/− mice displayed an increase in cell proliferation. Data shown represent the mean±SEM of 7–8 mice per group. *P < 0.05; **P < 0.01; ***P < 0.001 vs PDE4B + / + (two-tailed Student’s t-test).	complete

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